Experts in autocracies have pointed out that it is, unfortunately, easy to slip into normalizing the tyrant, hence it is important to hang on to outrage. These incidents which seem to call for the efforts of the Greek Furies (Erinyes) to come and deal with them will, I hope, help with that. As a reminder, though no one really knows how many there were supposed to be, the three names we have are Alecto, Megaera, and Tisiphone. These roughly translate as “unceasing,” “grudging,” and “vengeful destruction.”
I’m sure it’s no surprise to anyone here that, since about forever, medical studies have limited their subjects to men – or that this has produced a disparity in the quality of medical treatment received by females as opposed to males. Some medical misconceptions about women are comparable to misconceptions about people of color – both groups are assumed (subconsciously – I am not accusing any doctors of doing this deliberately) to be exaggerating their pain. Any woman can tell you stories.
But one positive result of CoViD-19 may be that it has brought attention to a big sex difference in immunity. Roughly equal numbers of men and women get the virus (with symptoms) in every age group. But, in every age group, about twice the percentage of men die. This has immunologists (one of whom wrote this paper) looking hard for answers.
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COVID-19’s deadliness for men is revealing why researchers should have been studying immune system sex differences years ago
Adam Moeser, Michigan State University
When it comes to surviving critical cases of COVID-19, it appears that men draw the short straw.
Initial reports from China revealed the early evidence of increased male mortality associated with COVID. According to the Global Health 50/50 research initiative, nearly every country is now reporting significantly higher COVID-19-related mortality rates in males than in females as of June 4. Yet, current data suggest similar infection rates for men and women. In other words, while men and women are being infected with COVID-19 at similar rates, a significantly higher proportion of men succumb to the disease than women, across groups of similar age. Why is it then that more men are dying from COVID-19? Or rather, should we be asking why are more women surviving?
I am an immunologist, and I explore how stress and biological sex can impact a person’s vulnerability to immune-mediated disease. I study a specific immune cell called the mast cell. Mast cells play a pivotal role in our immune systems as they act as first responders to pathogens and orchestrate immune responses that help clear the invading pathogens.
Our research shows that mast cells from females are able to initiate a more active immune response, which may help females fight off infectious diseases better than men. But the trade-off may be that women are at higher risk for allergic and inflammatory diseases. Recent evidence indicates that mast cells are activated by SARS-CoV-2 which causes COVID-19.
Some clues to why females have higher survival rates may be found in our current understanding of differences in the immune systems of men versus women.
Could sex differences in immune system play a role?
In general, females have a more robust immune response than men which may help females fight off infections better than males. This could be a result of genetic factors or sex hormones such as estrogen and testosterone.
Biological females have two copies of the X chromosome, which contains more immune genes. While the genes on one X chromosome are mostly inactive, some immune genes can escape this inactivation, leading to double the number of immune-related genes and thus double the quantity of certain immune proteins compared with biological men who have only one X chromosome.
Sex hormones such as estrogen and testosterone can also impact the immune response. In one study, researchers showed that activating the estrogen receptor in female mice provided them protection against SARS-CoV. And there is an approved clinical trial that will examine the effects of estrogen patches on the severity of COVID-19 symptoms.
It is, however, interesting that the current data showing that women have better survival rates than men applies to even men and women in the 80-plus age group, when hormone levels in both sexes equalize. This suggests that factors other than adult sex hormone levels are contributing to sex differences in COVID-19 mortality.
Androgens, a group of hormones – including testosterone – that are best known to stimulate the development of male characteristics and can cause hair loss, have also received recent attention as a risk factor for COVID-19 in males. In a study conducted in Italy, prostate cancer diagnosis increased the risk for COVID-19. However, prostate cancer patients who were receiving androgen-deprivation therapy (ADT), a treatment that suppresses the production of androgens which fuels prostate cancer cell growth, had a significantly lower risk for SARS-CoV-2 infection. This suggests that blocking androgens in men was protective against SARS-CoV-2 infection.
It is unknown how ADT works to reduce infection rates in men and whether this has been shown in other countries has yet to be determined. Testosterone, which is an androgen hormone has immune-suppressive effects so one explanation could be that ADT might boost the immune system to combat SARS-CoV-2 infection.
There is also evidence that males and females have different quantities of certain receptors that recognize pathogens or that serve as an invasion point for viruses like SARS-CoV-2. One example is the quantity of angiotensin converting enzyme 2 (ACE2) receptors, which SARS-CoV-2 binds to in order to infect cells. While there is currently no conclusive evidence for a role of ACE2 receptors impacting sex differences and the severity of COVID-19 disease, it remains a potential contributing factor.
Gender, sex and COVID-19 risk
A number of factors can interact with biological sex to increase or decrease one’s susceptibility to COVID-19. Another major factor is gender, which refers to social behaviors or cultural norms that society deems appropriate. Males may be at increased risk for severe disease, because in general, they tend to smoke and drink more, wash their hands less frequently and often delay seeking medical attention. All of these gender specific behaviors may put men at higher risk. While there is no current data yet on how gender plays a role in COVID-19, it will be a critically important factor to account for in order to understand sex differences in mortality.
Age, psychological stress level, coexisting conditions such as obesity, diabetes and cardiovascular disease can also interact with biological sex to increase disease.
While COVID-19 highlights the importance of biological sex in disease risk, sex biases in disease in general is not a new concept. COVID-19 is just another example of a disease that will be added to the growing list of diseases for which males or females are at increased risk.
A history of male-biased research
You might be wondering that if biological sex is so important, then why don’t we know what is causing disparities in disease prevalence between the sexes and why are there no sex-specific therapies?
One major reason is when it comes to being included in scientific research, it is mostly males who have been studied.
This disparity between biological sex differences in research has only recently been remedied. It has only been in the last five years that the National Institutes of Health has required sex difference data to be collected for all newly funded preclinical research grants.
While there may be several reasons for choosing one sex over the other in research, the huge disparity that now exists is likely a major reason why we still know relatively little about sex differences in immunity, including the current COVID-19 pandemic.
This has clearly hindered advancement of women’s health, but also has negative consequences for men’s health. For example, given the biological differences between the sexes, it is very possible that drugs and therapies will have different effects in females than males.
Biological sex is clearly a major factor determining disease outcomes in COVID-19. Precisely how your biological sex makes you more or less resilient to diseases such as COVID-19 remains to be elucidated. Future basic research with animals and clinical trials in people need to consider biological sex as well as interactions with gender as an important variable.
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Adam Moeser, Matilda R. Wilson Endowed Chair, Associate Professor of Large Animal Clinical Sciences, Michigan State University
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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Alecto, Megaera, and Tisiphone, as I was reading, I was interested to know whether anyone had compared the death rate of corona virus patients who were prepubertal boys as opposed to the death rate in prepubertal girls … but that was not mentioned. I hope that’s because there are not enough cases to examine – but if so I fear that’s not going to stay valid. At any rate, I hope some good comes of the investigation and research that is being done. Give the researchers some pats on the back, or however you prefer to encourage us poor humans.
The Furies and I will be back.
13 Responses to “Everyday Erinyes #219”
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Saw this earlier, and found it fascinating Who is the “stronger sex?” the bias is like that of many psychology studies, in that they reflect the responses of overwhelmingly white college students.
Excellent, educational information, and post, Joanne.
Thanks so much for getting it out here. Still reading.
Thanks Joanne: Illuminating. I remember speculation on the earliest Wuhan data out of China that the gender difference probably attributable to the significantly higher smoking rates in men vs. women there. As I read, I realized the centurians who I’d read about recovering were all women.
Both a very interesting article and (given my Y chromosome) also anxiety-provoking.
Clearly at lot more research will be needed to reach any conclusions, because we know “correlation does not imply causation.”
So true. And there is a lot to learn. I personally was fascinated to hear that auto-immune disorders are more common in women than in men, mainly because I have one, besides allergies – pretibial myxedema. But also, every time I’ve heard of someone having lupus, it certainly seems like it’s always a woman. It would appear having more mast cells can be a mixed blessing.
JD:
“It would appear having more mast cells can be a mixed blessing.”
I was very tempted to note just that – but glad it came from the distaff side.
I suppose, in general, the more one has of anything, or the more kinds of things one has, the more ways there are for things to go wrong. (I also suppose the main reason that we know any of this is that for the last, what, 75-100 years, people have been surviving bacterial infections, which has allowed everyone’s immune system to develop further than they once did.
Agree with others, fascinating article. I hear of the Covid-19 daily stats each afternoon from our local city council. They do tell us how many male and females.
Like you pointed out, men do seem to be more into smoking and drinking than women.
Plus women do seem to be somewhat more active than men, in many ways.
Thanks for the information, Joanne
Very interesting article indeed, Joanne.
Though not completely unexpected to me as I was taught that, although men refer to women as the weaker sex, it is in fact the opposite and something mother nature tries to compensate for by biasing the natural ratio between males and females at birth slightly towards the male sex, which is estimated to be about 1.05 or 1.06.
The reported findings that mast cells from females are able to initiate a more active immune response may have something to do with that. Evolutionary speaking, the greatest threat to a female’s life is childbirth, while that of a male is another male. It seems logical that it would benefit the species if women were better equipped to ward off disease and carry their offspring to term.
Thanks for a thought provoking article, JD. When it comes to sex, I wonder if remembering how would increase my risk.
Based on comparisons they did of men and women in their eighties, probably not.
Time to put on my memory hat, then!
fascinating, thank you.