A possible link between the menopause and Covid-19 needs to be investigated, researchers have said, with some evidence suggesting that falling oestrogen levels could leave older women at increased risk from the disease.
Men are at greater risk of severe Covid, and dying of the disease, than women but recent research has suggested that in women, infections and long-lasting symptoms might be more common among those who have gone through the menopause.
Such findings have raised the question of whether hormones such as oestrogen might play a protective role – hormones that are at higher levels in women than men, but wane as women go through the menopause.
“It’s a good question about whether hormones could play a part, or other differences with age and gender – such as the immune response,” said Dr Claire Steves, a member of the Covid symptom study app team at King’s College London.
In one study based on reported symptoms, yet to be peer reviewed, Steves and her colleagues found post-menopausal women were at greater risk of having Covid than non-menopausal women of similar age and body mass index. There are also some hints that the former may be at greater risk of more severe symptoms.
The team also found that users of the combined oral contraceptive pill – which contains oestrogen – had a lower risk of Covid than their peers.
In another study, the team found women were at greater risk of having “long Covid” than men, with women aged 50 to 60 at greatest risk of developing lingering symptoms.
Meanwhile, a study from China found menopausal women with Covid spent less time in hospital than non-menopausal women once age and disease severity were taken into account.
Some have pushed back against the long-Covid findings of Steves and colleagues, noting the results are based on people who had a positive Covid test, meaning it did not fully consider those who had Covid at home.
But Steves said the team found long Covid in a wide range of people, including younger people and men.
“It’s certainly not just an issue in women over 50,” she said. “It’s just that this was the group the rate was highest in.”
Dr Betty Raman of the University of Oxford said both age and sex appeared to be important when it came to Covid.
Raman and her colleagues are following up a cohort of 58 people who were hospitalised for at least two days with coronavirus. Among this cohort, 41% are women, 67% of whom are over 50 years old. But of the 55 participants who completed a subsequent survey, 50% of men and 61% of women had moderate to severe fatigue. What is more, 10 of these 14 women were over 50.
“There isn’t any strong evidence that the presence of oestrogen or the lack of oestrogen is either protective or harmful to individuals in terms of their response – we don’t have any firm evidence,” said Raman.
But she added: “We do have correlations and associations between levels of hormones and severity of disease, and of course sex of the individual and severity of the disease.”
Raman added that oestrogen was known to be beneficial in some other diseases – including coronary artery disease, which is more common in men than women.
James O’Keefe, a US cardiologist and professor of medicine at the University of Missouri-Kansas City, agreed. “We can strongly suspect that the oestrogen is protective because we know from other studies that oestrogen helps to improve some aspects of immunity. Oestrogen also helps to support optimal function of the lungs and the cardiovascular system,” he said, adding that testosterone was overall an immunosuppressant.
However, he added: “I don’t think we know enough about Covid and those who are at risk for the long-haul complications to speculate on why women are more predisposed to it than men.”
Raman said one problem was that long Covid is ill-defined, while a third of patients in her study needed ventilation, making it hard to know if the lingering symptoms were down to the disease itself. In addition, men are more likely to die from Covid. “It is possible the reason we are seeing this disproportionate prevalence, at least in the hospitalised cohort, is because of the survival bias that you have,” she said.
It is also known that perimenopausal women often experience symptoms such as fatigue, making it hard to identify which symptoms are down to Covid itself.
“What we are lacking so far are good, [matched] control groups,” said Raman.
Dr Louise Newson, a menopause specialist and founder of the Menopause Charity, agreed there could be a number of reasons why post-menopausal women appear to be at greatest risk of developing long Covid.
But she said there re a number of clues that suggest hormones and Covid interact, including that many women with long Covid have reported changes to their menstrual cycles after catching the virus, with their Covid symptoms worst when their hormone levels are lowest.
“We also know that the ACE2 receptors are affected by Covid infection and there are a high proportion of these receptors in the ovaries. It is very likely that this has a direct consequence on lowering oestrogen and testosterone levels which are hormones produced by ovaries,” she added.
If falling oestrogen levels do leave women more at risk of Covid, a study by Newson, Steves and colleagues suggested the controversial hormone replacement therapy (HRT) might not help, although it is something the team are looking to explore further, with anecdotal evidence suggesting a potential benefit.