Tag Archive for: hormones

Oral Contraceptives and Emotions: How Progestin can Influence Mood and Socio-Emotional Cognition

Author: Minhal Mussawar, University of Saskatchewan | Editors: Romina Garcia de leon, Shayda Swann  (Blog Coordinators) 

Published: September 23rd, 2022

Oral contraceptives are one of the most commonly chosen forms of contraception in Canada. Reasons for this include high therapeutic value and status as a cheap and accessible form of contraceptive, but also for their health benefits, such as managing dysmenorrhea, premenstrual syndrome and reducing the risk of ovarian cancer. Hence, they represent a cost-effective way of mitigating and treating many health conditions. Unfortunately, they also come with a number of negative side effects, including nausea, headaches and cramping, and can increase the risk of cardiovascular conditions in some users. Moreover, the likelihood of developing serious complications, such as venous thromboembolisms, can vary depending on whether an individual is taking a combined or progestin-only pill, meaning that certain patient populations may fare better on one type of pill than another. Another health condition that may be influenced by oral contraceptive type is breast cancer, where women who use high-dose estrogen pills are at a higher risk of developing breast cancer than those who use lower doses.

Evidently, there is plenty of research regarding the physiological effects of oral contraceptives on its users. In an age where female participants are being studied more and the scientific community has acknowledged its history of favouring male participants in the past, this type of research has become paramount as it represents a push towards sex inclusivity in literature that was previously non-existent.

Yet, while progress has been made with respect to studying the physical effects of oral contraceptives, less can be said about their cognitive and psychological effects. One study reported mood differences associated with the use of combined oral contraceptives, and another noted differential effects on verbal memory based on whether participants were in the active pill phase (pills that contained the active ingredients of estradiol and progestin) of their birth control or the inactive phase (“placebo” pills). However, aside from generalised research on the effects of combined pills, few studies have assessed the extent birth control can impact a person’s cognitive functioning. Even fewer have separated the effects of ethinyl estradiol and progestin (the two active ingredients in all combined oral contraceptives) and independently studied their effects. Our study aimed to address this issue; we wanted to see how one component of the combined oral contraceptive pill – progestin androgenicity – can affect various cognitive and emotional parameters.

Progestin androgenicity refers to the extent to which a progestin is structurally related to the androgenic hormone testosterone; progestins with high levels of androgenicity tend to bind to testosterone receptors in the body with a higher affinity than their anti-androgenic counterparts. This, unsurprisingly, leads to more androgenic side effects when taking the pill. For our study, we first looked at the existing literature on progestin type and cognitive differences. We found a few papers that suggested users who took oral contraceptives with androgenic progestins performed worse on verbal memory tasks than those who took anti-androgenic contraceptives. Other research suggested that individuals who took oral contraceptives with androgenic progestins performed better on visuospatial and socio-emotional tasks.

Based on this research, we anticipated that individuals taking highly androgenic progestins would yield higher and more accurate scores on social-emotional cognition (emotion recognition and rejection sensitivity) relative to non-androgenic progestin users. Our findings aligned with this hypothesis, as we found that androgenic progestin users were better at recognising negative emotions such as facial expressions of sadness, fear and disgust. Interestingly enough, androgenic users also reported feeling significantly more stressed when measuring their mood on a visual analogue scale compared to anti-androgenic users. Overall, these results indicate that highly androgenic progestins may have a negative psychological effect on users versus anti-androgenic users.

 

 

                                                                

Figure 1. Progestin androgenicity effects on mean stress scores on the Visual Analogue Scale (standard error bars shown). Androgenic users reported feeling significantly more stressed throughout the lab session.

 

Figure 2. Average rate of correct identification (%) for sadness on the Emotion Recognition Task (standard error bars shown). Androgenic users were significantly more accurate at identifying sadness compared to anti-androgenic users.

These findings are consistent with previous research on androgenic hormones and socio-emotional cognition; studies have found correlations between social threat identification and testosterone. Additionally, anti-androgenic progestins have historically been used to treat negative mood in premenstrual syndrome; this makes the association between negative mood and androgenic progestins expected.

So how do we interpret these findings on a larger scale? Well, there are two key implications that arise from this study, the first of which comes from the association between negative mood and androgenic progestin use. As noted earlier, oral contraceptives with anti-androgenic progestins can be used to treat negative mood symptoms in premenstrual syndrome. With this in mind, it may be worth considering progestin androgenicity when prescribing oral contraceptives to this patient population, as well to patients who may be at risk or have a history of depression and anxiety as androgenic progestins could potentially exacerbate any negative thoughts they may have. The second implication comes from how oral contraceptives are viewed in general. Since they are  very common drugs, it can be easy to underestimate their effects, as a result, people who may consider using them may not appreciate how much of an impact they may have on their socio-emotional functioning. In fact, it is not uncommon to hear about people “just going on birth control” once they become sexually active, and while implementing contraceptive measures ought to be encouraged, those who are considering using them should still be informed about their potential side effects. The same goes for people who expect their partners to start oral contraceptives.

This research represents the tip of the iceberg when it comes to studying the psychological effects of oral contraceptives. There are a multitude of other factors at play that should also be considered in light of this study; for example, ethinyl estradiol dose can induce its own effects on users, independent of progestin type. This is also something that we hope to look into further with our research, where our next steps involve assessing the role estrogen plays on the same parameters. We look forward to seeing the results and hope it can help elucidate the role each hormone can play.  

 

Mind Over Menstruation: How the Menstrual Cycle Influences Brain & Behaviours

 

Author(s): Kiranjot Jhajj (B.Sc., University of Northern British Columbia) and Annie Duchesne (Ph.D., University of Northern British Columbia) Editors: Negin Nia & Romina Garcia de leon (Blog Co-coordinators)

Published: July 29th, 2022

Research investigating relations between the menstrual cycle and women’s behaviours has a controversial history. It is rooted in attempts to demonstrate that women are biologically programmed to be less intelligent, more caring, and more emotional than their male counterparts. While this research and rationale has long been debunked, today’s growing interest in studying the brain and behavioral correlates of the menstrual cycle exists to understand how this phenomenon brings a distinct source of variability to people who menstruate, which remains understudied in fields such as neuroscience.  

One dimension of the menstrual cycle that has been increasingly studied in relation to brain and behavior is its hormonal dimension, which encompasses the variations in the ovarian hormones, estrogens and progesterone (see Figure 1), and how these influence reproduction, brain, and behavior. The menstrual cycle can also be investigated as a social phenomenon, which encompasses the attitudes, beliefs, and stigma around menstruation. However, the social and hormonal dimensions of the menstrual cycle are rarely investigated together. Little is known about how the social framing of the menstrual cycle can influence the hormonal dimension and vice versa. We introduce an integrative view of the menstrual cycle as both a hormonal and social phenomenon.

 

Figure 1. Hormone fluctuations across the menstrual cycle. “File:Estradiol.Cycle.jpg” by The original uploader was Ekem at English Wikipedia. is licensed under CC BY-SA 3.0.

The menstrual cycle as a hormonal phenomenon 

While it is established that the menstrual cycle and the related hormonal fluctuations are at play, a significant role in reproduction, a growing body of literature also reveals a role of these hormones in brain and behavior in humans and animals. However, these effects of ovarian hormones on the brain and psychological changes across the menstrual cycle vary. Several studies reveal a dissociation between cycle phase effects and hormonal effects on brain and behavior. One such study found that women with greater baseline inhibitory control were slower to react during the preovulatory phase compared to menses, while those with lower baseline inhibitory control showed the opposite pattern. Such evidence suggests that ovarian hormones may not be the only factors contributing to the effects of the menstrual cycle phases on brain and behavior. Additional factors may also be involved, specifically the related social constructs.   

The menstrual cycle as a socially constructed phenomenon 

The menstrual cycle is constantly surrounded by stigma. The stigmatized understanding of menstruation is evident across different societies, promoting ideas of menstruating women being unclean and unable to function normally. Further, menstruation stigma leads to negative impacts on those who menstruate, such as hypervigilance, self-consciousness around the need to hide menstruation, and the experience of shame related to menstruation. These stigmatized views can translate to various sources of stress for those who experience menstruation.

The stigmas around menstruation have consequences on how women perceive their periods. For instance, a study investigating women’s beliefs about menstruation in Mexico revealed that participants holding stereotypical views on women believed that menstruating people should follow specific guidelines about daily activities because they can be more fragile during this period. Participants who reported holding misogynistic opinions about women believed that menstruation is “annoying” and that people should hide menstruation to avoid embarrassment. Beliefs about menstruation tend to be negative, putting menstruating people in an unfavorable and restrictive state.  

 The influence of attitudes and beliefs about the menstrual cycle is not limited to menstruation alone, as they can also affect women throughout their cycle (see Figure 2). For instance, one study found that the mere request for menstruation-related information acted as a stereotype threat that influenced cognitive performance. While stigma can be related to the experience of menstruation, this study shows another similar source of stress, rooted in the awareness of one’s menstrual cycle. Taken together, this evidence outlines the importance of the social dimensions of the menstrual cycle when investigating its effects on the brain and behavior.

 

Figure 2. Hormone fluctuations across the menstrual cycle, with the addition of where stigma regarding menstruation may be prominent. Menstruation stigma can occur during menstruation itself, whereas menstrual cycle stereotype threat could arise whenever menstruation is mentioned, which is not tied to any specific cycle phase. “File:Estradiol.Cycle.jpg” by The original uploader was Ekem at English Wikipedia. is licensed under CC BY-SA 3.0.

The hormonal meets the social dimension

A majority of the research on the menstrual cycle tends to focus on either its hormonal or social dimensions. We believe that there is benefit in approaching the menstrual cycle as an integrated biopsychosocial phenomenon. Within an integrated approach, it is possible that the stigma activates stress systems and translates to a physiological phenomenon to influence brain and behavior. For example, one study shows that the expectation of stigma based on one’s identity can physiologically alter how one reacts to social stressors. Thus, effects of the menstrual cycle on brain and behaviour may partially be attributed to the stress-related effects of menstruation stigma and menstrual cycle stereotype threat. 

Another layer of integration between the social and hormonal dimensions of the menstrual cycle involves the interaction between their respective endocrine systems. Research shows that the stress and ovarian systems can interact, either through mutual inhibition or activation. Through the activation of stress systems, stigma and stereotype threat related to menstruation can influence the hormonal dimension of the menstrual cycle. Inversely, it is also possible that variation in ovarian hormones regulates how individuals react to menstruation stigma and menstrual cycle stereotype threat. Then, instead of considering the social and hormonal aspects as two independent dimensions by which the menstrual cycle influences brain and behavior, it is more productive to study the interplay between  the social dimensions and the biological aspects of the menstrual cycle. 

Conclusion

As research on the influence of the menstrual cycle on brain and behavior increases, there is an opportunity to consider the multiple dimensions of this phenomenon and how they interact to influence brain and behaviours. The menstrual cycle is a biological occurrence situated within various layers of social context. While ovarian hormones can influence cognition throughout the menstrual cycle, it is also vital to consider that these changes may be affected by the stigma associated with specific phases of the menstrual cycle, which in turn can influence the physiology of people who menstruate. 

COVID-19 Differences Between Men and Women

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).

 

 

Behind the Science: Politics of Women’s Hormonal Disorders

Authors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators) || Interviewing: Shruti Buddhavarapu, B.A., M.A., University of British Columbia 

Published: August 27th, 2021

There is no single definition of polycystic ovarian syndrome, or PCOS. But what we do know is that this complex disease is one of the most common hormonal disorders in women of reproductive age.

In this month’s article for our Behind the Science Series, author and researcher Shruti Buddhavarapu discusses her master’s work on the medical and gender politics of PCOS in India.

How did you become interested in women’s health research? How did you decide to research PCOS in India?

I started showing PCOS symptoms around the age of 14-15 but it took another 10 years before I officially received a diagnosis. The journey from first noticing my symptoms to finally finding a method of managing the symptoms that aligned with my views was brutal. Women are constantly gaslit in the doctor’s office. We have to toe the line between trying to be “The Good Patient”, and fighting the condescension of a system that naturally distrusts our symptoms and our accounts of those symptoms. I was also hugely disappointed by the number of doctors who asked me to come back to them when I wanted kids—not if. It was as if PCOS only mattered because it threatened my ability to reproduce.

My research on PCOS uses critical discourse theory and analysis which have been important tools for me all through academia. This methodology looks at what the language we use tells us about the social context we’re in. It assesses the ways in which the words we use (consciously and unconsciously) create and maintain social inequalities and systems of power.

Now it seems natural that I’d apply those skills to expose the professional, political and personal networks that underpin an individual experience of a particular medical syndrome. 

How would you explain your research in simple terms?

My PCOS research studied the language and knowledge around illness and health. The paper I published in the Journal of Medical Humanities was a modified version of my Master’s research. I look at the lived experiences of folks with PCOS, especially in India. Which is to say, outside of medical discourse and doctor prescriptions, what does it mean to live with PCOS in the day-to-day? I wrote about how the lack of a known cause for PCOS allows for there to be convenient assumptions on womanhood and femaleness from those who benefit from patriarchy. It used to be common to tell women with PCOS that they invited the syndrome upon themselves due to a “Westernized lifestyle and diet.” I’ve heard this many times from doctors myself. Add to it the horror that women with PCOS may be infertile, which really threatens this nationalist idea of the pure, untarnished, un-Westernized and thus fertile and healthy Indian woman. This scare-mongering and moral policing of folks with PCOS serves no one. It focuses entirely on the wrong thing — the potential of women as mothers as opposed to individuals.

What do you think is the most important impact of your research?

Back in 2015, when I wanted to perform a critical discourse analysis of folks’ experiences with PCOS through their notion of femaleness/femininity, I was surprised to find a huge lack of material. Most academic writing on PCOS was medical with only a handful of sociological articles. So I was creating the literature I wanted to cite. I try to push the boundaries we take for granted in medical literature by bringing attention to the unrelenting but often invisible biases that are present in medicine. 

Why do you think we need to focus on women’s health in research?

I think there’s an urgent (mind you, it’s been long overdue, like centuries overdue) need for science and research to reflect the spectrum of a variety of lived experiences.

Basically, we need to democratize research. We need queer, non-binary, trans experiences to show up in our research, and we need them to be researchers. For too long, science has been the repository of colonial violence, centring a white, cis-male experience. Did you know that the Ferriman-Gallwey index (to measure hirsutism—a condition that results in “excessive, male-pattern” hair growth in women) was built on a caucasian model of “hairiness”? So for a long while, women of colour were judged on a scale that just didn’t factor in their genetic histories. 

Why is your work and women’s health research important and needed in India?

While PCOS is something that affects folks worldwide, India has one of the highest rates of the syndrome. There are ties linking this to the alarming rates of type 2 diabetes in India. (There is a close connection between PCOS and insulin resistance—often a precursor to diabetes.) 

In many ways, I want to say my research is important in India because this is where I live, and I cannot separate my location from my politics. But it also intuitively is where I need to be with my research because such a large population has PCOS in India. 

Did you face any challenges conducting your research or increasing awareness of your findings?

In my case, the biggest impediment to my research was the lack of previous research. But I knew this while going in, so I was prepared for it. 

Since one of my key arguments was that there was so little of it to go around (outside of scientific discussions), it only served my argument’s larger purpose. With my thesis, I wanted to say: “Here’s all the research we have so far. It is pitiful and has a history of being biased towards patriarchal ideas of womanhood. We need to change our language about PCOS to make it accessible to everyone, without bias.”

What are you working on now?

I recently published a creative non-fiction memoir about rootlessness, chronic illness and growing up and dating as a woman in urban India. It’s called “The Weight of a Cherry Blossom”. I’ve also been involved in a couple of pop-culture projects as a PCOS specialist/researcher—Buzzfeed, Mid-Day, Mumbai Mirror, Firstpost and A Sense of Place on Roundhouse Radio Vancouver. 

For Firstpost, for instance, I wrote a series of reimaginings of popular classics, such as Alice in Wonderland and Jane Eyre, where the protagonists have PCOS. It is tongue-in-cheek and irreverent but was a wonderful way to open conversation about PCOS. I would like to write more about the networks of chronic illness, capitalism and notions of productivity in the workplace. 

What makes you excited about the future in women’s health research?

That it’s changing! So radically, so exponentially, so determinedly. When I started research on PCOS in 2015, there was very little material in and outside of academia on the topic. Now, the number of youtube channels, IG accounts dedicated to illness discourse and women (always inclusive of trans folk) and non-binary folks’ health is so affirming. There’s so much more information coming from folks with lived experiences and women’s health researchers to the general public. 

Where would you like people to connect with you?

I’m happy to chat/connect on shrutirao1988@gmail.com or shrutirao.com! 

Barriers in Transgender Research

Author: Keila Turino Miranda, BSc Honours in Pharmacology, University of Alberta, Twitter: @keila_turino | Editors: Alex Lukey and Arrthy Thayaparan (Blog Coordinators) 

Published: October 29th, 2020

The transgender community is a growing and underserved population estimated to reach over one million in the USA alone. In comparison to their cis-counterparts, where sex (biological attributes) and gender (socially constructed roles, behaviours, expressions and identities) align, transgender individuals experience gender dysphoria. Gender dysphoria is defined as a persistent feeling that an individual’s biological sex does not match their gender identity. As a result, transgender individuals experience severe distress, which significantly impairs their ability to function in society. This condition occurs on a spectrum, where transgender individuals are at the extreme end. This clinical diagnosis results in gender-affirming hormone therapy initiation, where feminization or masculinization goals are initiated. For transgender women, gender-affirming hormone therapy consists of the use of exogenous synthetic estrogens often in conjunction with anti-androgens to promote feminization (breast growth, decreased facial and body hair, genital atrophy, etc.) and minimize the effects of endogenous androgens like testosterone (deepening of the voice, differential distribution of body fat and muscle).

Protocols for Transgender Care

Estrogen gender-affirming hormone therapy formulation, dose, administration route, and co-administration with anti-androgens vary on individual goals for transitioning. Higher doses may be used for a more pronounced transitioning, while lower doses may be used if the individual is predisposed to other health complications. Additionally, the administration route may vary based on personal preference or recommendation by the health care practitioner. An example of this is seen in the preference for non-oral (transdermal patch, intravenous injection, etc.) estrogen gender-affirming hormone therapy over oral routes. This preference is a direct result of experimental data in cis-women showing that oral estrogen therapy, whether for contraceptive or postmenopausal use, is associated with an increased cardiovascular risk compared to non-oral estrogen. As a result, transgender women over the age of 45 or with a predisposition to cardiovascular disease are prescribed non-oral forms of estrogen to minimize risk. However, no current research suggests that this finding is also consistent or applicable to transgender women. Therefore, protocols for the care of transgender women have been modelled after research done in cis-women populations. However, this can become problematic as these two populations differ by biological attributes, societal pressures and other factors. Whether or not this is appropriate can only be determined through further research into gender-affirming hormone therapy routes of administration.

Current Research in the Transgender Field

Transgender women face healthcare disparities and have higher rates of substance use disorders, depression, anxiety and suicidality. Moreover, transgender women receiving gender-affirming hormone therapy are disproportionally affected by cardiovascular disease. Despite the growing number of the transgender population and the increased prevalence of gender-affirming hormone therapy use, research outside of HIV prevalence is limited. A newly published study on HIV prevention reported the positive impact greater social support in discussing HIV-related issues has on HIV prevention knowledge. These results point to the growing body of thought regarding minority stress. Stigmatized minority groups, such as the transgender population, show chronically elevated levels of stress. In addition to the limited research seen in transgender health, there is a lack of acknowledgement of minority stress and its implications on disease progression.

Barriers in Transgender Research 

As an up-and-coming field, transgender research is limited by its heterogeneity in terminology and study quality. Researchers in this field must often consider the variability and advancement of the use of transgender terminology in active avoidance of transphobia. For example, outdated terms such as she-male, cross-sex and trans-sexual are often seen in previous literature, and Alberta Health Services contraindicates its use. Additionally, systematic reviewers in the field must consider these terms to capture relevant transgender research adequately. 

As previously discussed, there is great variability in gender-affirming hormone therapy dose, formulation and administration route. As a result, there is significant heterogeneity in available studies, which is a barrier for appropriate quantification of their effects on transgender health and disease progression. Route of gender-affirming hormone therapy administration is postulated as partly responsible for this as the pharmacokinetics (drug absorption, distribution, metabolism and excretion) and pharmacodynamics (drug action and mechanism) vary. Pharmacokinetics is an important consideration as oral and non-oral therapies are subjected to differential levels of metabolism, total systemic dose, excretion rates, and other variables, which affect their drug actions and mechanism (pharmacodynamics). These are vital considerations as drug interactions affect disease progression, and in long term cases, morbidity and mortality. 

In addition to experimental group variability, there are also inappropriate control groups, thus serving as an additional barrier. The psychological benefits provided by gender-affirming hormone therapy renders the use of placebo groups unethical. Researchers are limited to recruiting transgender individuals who have not initiated gender-affirming hormone therapy in search of an appropriate control. Although it would be unlikely to recruit these individuals and abstain from therapy initiation throughout the study, this would provide an appropriate control group as these individuals would share the same gender-identity. Additionally, researchers may opt to use cis-men as a sex (biological attributes) control. With this, studies looking to compare morbidity and mortality of diseases would be better equipped to assess transgender health as it pertains to gender-affirming hormone therapy use.

Cross-sectional studies aiming to obtain estimates of disease incidence and prevalence are limited by the inadequate collection of gender identity information in clinics and national surveys. This further prevents accurate and up-to-date epidemiological analysis of transgender health and serves as a further barrier for researchers and clinicians looking to address this population’s health adversities.

Future Directions 

Listed research barriers should be addressed through appropriate stratification of gender-affirming hormone therapy by dose, formation, administration route, and use of anti-androgens. Additionally, the implementation of appropriate control groups, cis-men and/or transgender women without therapy, is essential for adequate quantification of disease progression, morbidity and mortality. These modifications, accompanied by large cohort studies with sufficient follow-up, will allow for the advancement of clinical understandings and protocols.  Lastly, practicing clinicians caring for transgender patients should appreciate gender-affirming hormone therapy’s psychological benefits when considering the potential risks associated.

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Image courtesy of Denin Lawley on Unsplash

Why Paying Attention to Sex and Gender Will Advance our Knowledge on COVID-19

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.

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