As we wrote a little while ago, there’s some evidence to suggest that the sex hormone estrogen might help to protect against the severe effects of COVID-19. So, is this true?

To find out, we added a set of questions about hormones to our COVID Symptom Study app - including questions about the menopause, contraceptive pills and hormone replacement therapy (HRT) - and now the first results are in.

We speak to Dr. Karla Lee from King’s College London, who has been busy crunching the data, and Dr Louise Newson, advisor to NHS England, GP and menopause specialist, to provide insights into what we have found so far.‍

Why did we look into the link between hormones and COVID-19?‍

We know that men are more likely to suffer from severe symptoms of COVID-19 than women. This is true of many viral infections, including flu, SARS, and MERS, because men’s and women’s immune systems function differently.‍

The sex hormone estrogen, which is usually found in high levels in women before their meopause, interacts with the immune system in various ways, including influencing how many immune cells are produced and how they respond to infection.

Experts think that how your immune system responds to COVID could be vital in determining whether you suffer the worst symptoms of the disease. So it makes sense that having relatively high levels of immune-bolstering estrogen might be protective.

However, this potentially protective effect of estrogen doesn’t last a lifetime.

“We have seen through the app data that when women reach their mid to late fifties - which can correspond to the menopause - they too have worse COVID-19 symptoms, like men,” says Karla.  

Scientists think that the reason women have suffered less with COVID-19 may be related to female sex hormones, particularly estrogen, which drops during and after menopause.

When researchers in Wuhan, China, measured the estrogen levels of women admitted to hospital with COVID-19, they found that women with low estrogen levels were more likely to suffer severe symptoms than women with normal estrogen levels, supporting the idea that estrogen may be protective against the disease.

So if natural estrogen might be protective, what about hormone-based medications like HRT or the Pill?‍

Your data is helping us to find out more about hormones and COVID-19‍

"We hypothesized that the estrogen-containing combined oral contraceptive pill and hormone replacement therapy would offer a protective effect against COVID because they contain estrogen," says Karla. 

To find out if this idea was correct, we added some simple questions to our COVID Symptom Study app to explore the link between estrogen and COVID-19. 

To start with, we asked users which (if any) hormone treatments they are taking, including contraceptive pills, coils or injections, hormone replacement therapy, or hormones for gender transition. We also ask if they are having periods, have stopped having periods, or are pregnant.

By mapping the responses to these questions to daily symptom reports gathered through the app, we’ve been exploring the links between hormones and the severity of COVID-19 symptoms.‍

Menopause and COVID-19‍

“We looked at COVID symptoms in similar groups of women before and after the menopause and adjusted for other factors like age and BMI,” says Karla. “The data from 150,000 women aged 40-60, who were not taking HRT, supported our hypothesis that postmenopausal women have a higher chance of having symptomatic COVID than their premenopausal counterparts,” says Karla.  

However, postmenopausal women were not more likely to be hospitalized or need ventilation than those of a similar age who hadn’t yet gone through the menopause.

“By comparing women of similar ages, we could confirm that this was not merely an effect of age: it does appear that the higher estrogen levels associated with having an active menstrual cycle offer some protection in the fight against COVID-19”.‍

Hormone replacement therapy and COVID-19‍

Next, we compared the symptom data from postmenopausal women who were taking hormone replacement therapy with postmenopausal women who weren't.

“There are groups in the US that are using estrogen patches to see if that can make a difference in terms of COVID outcomes,” says Karla “So we thought that we might find a strong, protective effect from taking hormone replacement therapy, but that’s not what we saw.”

We did not find that hormone replacement therapy offered any protection against COVID-19. In fact, our data showed that women taking hormone replacement therapy were actually very slightly more likely to suffer symptoms of the disease. But there’s still a lot we don’t know.

“There are lots of different types of hormone replacement therapy, and women can be on a wide range of doses and can take HRT in multiple ways e.g. tablets, gels or patches. These contain various types of estrogen which are also likely to affect immune function in different ways. We did not determine the different types of HRT in this study. The duration of taking HRT is also likely to affect immunity and this was not studied in this research." Karla explains.

The simple questions asked through the app didn’t drill into this level of detail, making it difficult to draw robust conclusions about whether there is an effect or not.

“There is insufficient data from this study to determine whether or not taking some types of HRT provide some protection with respect to severity of COVID-19 infection. We know from other research that taking HRT lowers future risk of developing heart disease, diabetes and obesity.”, Dr Newson adds.

“For the majority of women, taking HRT provides more benefits than risks and these results do not affect this so women can still safely continue taking their HRT. Clearly more detailed research needs to be done in this area.”‍

The contraceptive pill and COVID-19‍

Finally, we looked at the data from 300,000 women between 18 and 45, who were taking the combined oral contraceptive pill (a.k.a. the Pill) and compared their reported COVID-19 symptoms with women of the same age who weren’t taking it.

“We saw a very strong protective effect from taking the contraceptive pill for this group of women," says Karla. "The Pill contains a higher concentration of estrogen than many hormone replacement therapies, which may explain the difference between the two treatments.”

This kind of analysis relies on having large datasets from many thousands of people, in order to make statistically robust calculations. 

Unfortunately, because only a small number of people taking hormone therapy for gender transition were using the app, there wasn’t enough data to reliably show whether there was an effect of these therapies on COVID-19 risk. ‍

In conclusion: Sex, hormones and COVID-19‍

• Men are more likely to suffer from severe COVID-19 than women, but the reasons why remain unclear.
• Scientists suspect that the hormone estrogen may have a protective effect against COVID-19.
• We analysed data from more than 500,000 women using the COVID Symptom Study app to see if there were any links between estrogen and COVID-19.
• Menopausal women were more likely to develop symptoms compared to women who were still having periods.
• We found that having regular periods was protective against COVID-19, as was taking the contraceptive pill. But hormone replacement therapy (HRT) did not seem to offer any protection.
• More data is needed to understand how hormones affect COVID-19 risk.
  

To keep doing research like this, we need our citizen scientists (like you!) to keep logging their health on a daily basis through our COVID Symptom Study app, even if you’re feeling well. So, if you haven’t already, download the app to get started!

Find out more:

• Sex differences in immune responses – Nature Reviews Immunology
• Considering how biological sex impacts immune responses and COVID-19 outcomes – Nature Reviews Immunology 
• Gender Differences in Patients With COVID-19: Focus on Severity and Mortality – Frontiers in Public Health 
• Do hormone therapies affect COVID-19? – COVID Symptom Study
• Sex, hormones and COVID-19: what do we know? – COVID Symptomn Study
• A Multi-hospital Study in Wuhan, China：Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection – MedRxiv
• Can Estrogen and Other Sex Hormones Help Men Survive Covid-19? – New York Times