How do hormones and sex affect coronavirus and COVID-19?‍

It has been widely reported that men are more likely to suffer worse symptoms and more likely to die from COVID-19 than women. But why?

We recently updated our COVID Symptom Study app to include questions about sex and hormones, including HRT and the Pill, to start to unpick how these important factors interact with coronavirus infection and COVID-19.‍

We’re hoping to have the first results to share with you next week, so watch this space.‍

To find out more, we spoke to women’s health expert, Dr Louise Newson, and our founder, Professor Tim Spector, to find out about role that the sex hormone estrogen plays in our immune systems, and the impact of menopause, pregnancy, and hormone replacement therapy on immunity. ‍

Why are men more affected by COVID-19 than women?‍

Men and women respond differently to many viral infections, including flu, SARS, and MERS. COVID-19, caused by the SARS-CoV-2 coronavirus, also appears to affect men more severely than women. 

“We know that women have a stronger response to infections, especially viruses, compared to men, and this is because we have different immune systems,” explains Louise.

Early research has shown that men are three times more likely to die from COVID-19 than women. A study in Ontario, Canada also showed that although more women were tested for the coronavirus, men were more likely to test positive, and had higher rates of hospitalization, ICU admission, and death.  

"It's very apparent from the data that we've seen that men are more commonly affected, more likely to be in the hospital, and also more likely to be in intensive care," says Louise. “When we analysed the data from our COVID symptom study, we also found that in the UK, men are more likely than women to need respiratory support after admission to hospital with COVID-19.”‍

Could estrogen have a protective effect against COVID-19?‍

The differences between responses to viruses in men and women are likely to come down to a combination of factors, including genetics and sex hormones. 

Researchers have suggested that the female sex hormone estrogen may play a particularly important role in protecting women against diseases like COVID-19. (Although estrogen is usually thought of as a female hormones, males also produce estrogen, but at much lower levels.)‍

Studies of SARS, a disease closely related to COVID-19, in female mice showed that blocking or removing estrogen increased the number of inflammatory cells in the animals’ lungs, making them more likely to suffer severe effects of the disease. 

Furthermore, researchers in Wuhan, China, measured the estrogen levels of patients admitted to hospital with COVID-19 and found that women with low estrogen levels tended to have more severe COVID-19 than women with higher levels of the hormone.

‍What about post-menopausal women? ‍

We know that the risk of dying from COVID-19 increases with age. And female sex hormones, including estrogen, decline gradually with time as women pass through the menopause. As a result, older women often have low estrogen levels. 

So what does this mean for their immunity and COVID-19 risk?‍

Results from our COVID Symptom Study app have highlighted that menopause may affect women's immunity to COVID-19. 

"At 55-60, we start to see what looks like an increase in females reporting symptoms of COVID-19, and that's exactly the time of the menopause and where there would be some estrogen deficiency," says Tim. 

Interestingly, the increase in COVID-19 symptoms with age for women occurs earlier than the increase with age seen for men, arguing that estrogen is having a protective effect against the disease earlier in life.‍

How does estrogen protect against COVID-19?‍

“Estrogen gets everywhere - it’s probably in every cell of the body, and it can have important effects on the immune system,” says Louise. For example, estrogen influences the number of immune cells that are produced, and affects the response to infection. 

“If the cells in our immune system don’t respond properly to a pathogen, then they produce chemicals called cytokines, which are good because they kill viruses, but then they can get out of control and damage tissue," Louise explains. Medical experts have associated these cytokine storms with the severe effects of COVID-19. 

Estrogen is thought to regulate immune response, ensuring that immune cells respond proportionately, and preventing over-reactions to infections like COVID-19 that may result in cytokine storms.  

If estrogen can dampen immune responses to COVID-19, prevent cytokine storms and decrease severe symptoms from the disease, this may point towards potential treatments for COVID-19. It might sound strange, but researchers in New York are already investigating whether short-term oestrogen treatment might help.

"In Stony Brook, New York, they looked at their data, and they realized that they didn't have any women who were pre-menopausal or any women who were taking hormone replacement therapy in their intensive care unit,” Louise says. “So they’re giving estrogen patches to men and women just for a week to see whether giving estrogen acutely can dampen down the immune response.”‍

The COVID Symptom Study app is finding out more about sex, hormones and COVID-19‍

"The effects of estrogen on immune responses can vary a lot depending on the disease," says Tim. "We don't know for definite whether estrogen is good or bad for COVID-19. It might depend on the individual, their own immune system and overall health, and other factors."

Currently, we don’t know how exactly estrogen levels, menopause, hormone replacement therapy, or pregnancy (when women naturally have very high levels of estrogen), might influence immunity to COVID-19 and disease outcomes. But we’re using our COVID Symptom Study app to find out.‍

We’ve updated the app to include questions about periods, menopause, pregnancy, and hormone treatments, including hormone-based contraception, HRT and cross-gender hormone therapy.  

The COVID Symptom Study is the largest ongoing coronavirus study in the world, so we hope that the resulting data will help us understand more about how estrogen and other sex-related factors influence COVID-19. You can explore our findings so far on our website. ‍

The run down on sex, hormones, and COVID-19‍

• Men are more susceptible to viruses, including coronavirus, and are more severely affected by COVID-19 than women
• This may be because estrogen increases immunity and offers a protective effect against the disease for women
• Post-menopausal women, who have low levels of estrogen, may be more at risk from COVID-19 then pre-menopausal women
• Researchers are investigating short-term estrogen therapy to help treat COVID-19
• We have updated our COVID Symptom Study app to learn more about the role of periods, hormones, menopause and pregnancy in COVID-19
  

Find out more:

• COVID-19 clinical characteristics, and sex-specific risk of mortality: Systematic Review and Meta-analysis – MedRivX
• Sex-specific differences in COVID-19 testing, cases and outcomes: a population-wide study in Ontario, Canada – MedRivX
• Gender Differences in Patients With COVID-19: Focus on Severity and Mortality – Frontiers in Immunology
• Key predictors of attending hospital with COVID19: An association study from the COVID Symptom Tracker App in 2,618,948 individuals – MedRivX 
• Why Covid-19 is different for men and women – BBC Focus
• Why are men more likely to get worse symptoms and die from covid-19? – New Scientist 
• Why Is COVID-19 Striking Men Harder Than Women? – Time 
• Sex Drives Dimorphic Immune Responses to Viral Infections – The Journal of Immunology
• Oestrogen and Coronavirus – MM
• A Multi-hospital Study in Wuhan, China:Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection – MedRivX
• Estrogen Regulation of T-Cell Function and Its Impact on the Tumor Microenvironment – Gender and the Genome
• Coronavirus ‘cytokine storm’: this over-active immune response could be behind some fatal cases of COVID-19 – The Conversation
• Sex Hormones Determine Immune Response – Frontiers in Immunology
• Can Estrogen and Other Sex Hormones Help Men Survive Covid-19? – The New York Times
• Do hormone therapies affect COVID-19? – COVID Symptom Study Research Updates

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