Almost from the beginning, scientists have been struck by the disproportionately higher numbers of men and older adults who have developed severe COVID-19 disease compared to younger individuals and women. Prior research has shown that in 37 of the 38 countries from which sex-stratified data was available, males were at a higher risk of death. Also, post-menopausal women are at increased risk of severe COVID-19. However, the biological underpinnings of this have been less visible.
Female Hormones and COVID-19
A new study published on the preprint server medRxiv* supports the intriguing hypothesis that female sex hormones are at least partly responsible for this phenomenon. This theory came to light in animal model studies of SARS-CoV, and MERS. Females have a more robust immune response to many viral infections. Estradiol and anti-Müllerian hormone (AMH) levels also mark high ovarian reserve and are inversely proportional to the severity of disease at any age. These findings have prompted a phase II trial of transdermal estradiol over the short term in men and post-menopausal women, and another testing oral progesterone in male COVID-19 hospitalized patients.
The current study by researchers from King's College London, University of Liverpool and Zoe Global Limited was aimed at contributing to an evaluation of the potential for estrogen treatment in COVID-19, by examining the presence of an association between high estrogen levels and lower levels of COVID-19 infection and severity in women. The source of the data is self-reported data from the UK. The outcome explored was the risk of symptomatic COVID-19 in recently menopausal women relative to premenopausal women over 40.
The researchers also looked at the effect of exogenous estrogen in the form of the combined oral contraceptive pill (COCP) on COVID-19-related symptoms and infection, and the effect of hormone replacement therapy (HRT) on COVID-19 positivity and symptom severity in women past menopause.
The Study Characteristics
The data was gathered from the COVID Symptom Study Smartphone Application which began gathering data on March 24, 2020, from self-reported COVID-related symptoms, basic user-health details such as age, height and weight, other risk factors as known, and daily updates on symptoms, visits to healthcare, testing for COVID, and self-isolation or other healthcare interventions.
The researchers in the current study also asked female users to report the use of COCP, HRT, and testosterone at one point, on May 7, 2020. Menstrual history was enquired about from premenopausal women, with age at menopause from others.
The study included 1.6 million women with a body mass index (BMI) between 20 and 35 kg/sq. m. The researchers examined the menopausal status, hormone use in the form of COCP and HRT, and symptoms related to COVID-19. Based on these, they predicted the chances of COVID-19 positivity, and disease severity was assessed by a history of hospitalization and respiratory support. Test results from a subset of women who had undergone viral RNA testing were also used to examine outcomes.
All outcomes were coded binomially, as I for positive and 0 for negative, including menopausal status, COCP use, HRT use, positive swab test, hospitalization, and respiratory support. Smoking, age, and BMI were coded as fixed effects. Five types of accelerated aging measures were also measured and compared to the symptoms and the predicted COVID-19 status.
Menopause and COVID Status
The researchers found that of about 150,000 women between 40 and 60 years, over 44,000 women were post-menopausal, with about 108,000 premenopausal controls. There were no women on HRT in this group. The rate of predicted COVID-19 was higher among post-menopausal women, with a higher rate of symptoms significant for COVID-19. Hospitalization and respiratory support also trended higher in this group, as did the chances of testing positive for the virus.
When this group was stratified by age, the predicted positivity was most strongly associated with the group between 45 and 50 years, who also had higher rates of anosmia, fever with chronic cough, and respiratory support.
COCP Use and COVID-19
The study also showed that the rate of predicted COVID-19 was lower in women using COCP, who also had a lower frequency of related symptoms and hospitalization. The test-positive trend was also lower in this group. Even when COCP use was excluded, there was a negative association with premenopausal status for predicted COVID-19 and reduced frequency of symptoms.
The age-stratified analysis showed the associations to be strongest for the 25-30 year group and the 40-45 year age group. In the former, the lower predicted positivity for COVID-19 was associated with COCP use.
HRT and COVID-19
The researchers also showed that the rate of predicted COVID-19 was higher in post-menopausal women on HRT, who also showed a higher frequency of related symptoms but not of hospitalization. HRT use was associated with a trend towards lower respiratory support and positive testing. The age-group analysis showed the effects to be highest in the 55-60 year age group.
Biological Aging and COVID-19 Symptoms
The researchers found, from their study of epigenetic aging markers in the subset of participants who were also part of the TwinsUK study, that these markers were most significantly associated with fatigue and muscle pain, followed by hoarseness of voice, skipping meals and anosmia. They point out that these results need to be confirmed given the small sample size.
Implications and Future Directions
The researchers point out that estradiol is involved in multiple innate immune components, and menopause, therefore, results in reduced immune function, among other changes. This has been shown in the fourfold risk of HIV among women over 45 years, and new HPV infections in older women who are not sexually active. Thus, the loss of this hormone after menopause might be one reason for the increased rate of predicted COVID-19 positivity.
A possible alternative explanation might be the biological aging that occurs after menopause, as hinted at by the TwinsUK subset of women in whom accelerated biological aging was correlated with increased frequency of COVID-19-related symptoms. This should prompt further research into how biological aging increases the risk of COVID-19 positivity and severity.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.