Age, Gender and COVID-19: A Complex Hormone Driven Interplay

November 19, 2020

Age is a well-known factor that influences the severity and fatality of COVID-19. In addition, male and female patients are known, at least anecdotally, to fare quite differently in the COVID-19 pandemic.  Why might this be, and can these observations help guide potential new treatments?  Does gender play a fundamental, causal role in disease severity?  If so, is there an age-dependency to the gender parameter?  More broadly, do age, biological sex and any potential gender-related factors (e.g., therapeutic hormone use) somehow interplay in a way that modulates the severity—and ultimate outcome—of a patient’s COVID-19 infection?

Motivated by these questions, Dean of the School of Data Science, Phil Bourne, and SDS Senior Scientist, Cam Mura, are part of an international team that has begun examining these possible interconnections.

In a new project with Drs Ute Seeland, Robert Preissner and Saskia Preissner (of the Charité–Universitätsmedizin Berlin), and including other collaborators in Germany and Italy, Bourne and Mura have helped analyze electronic health records (EHRs) of nearly 70,000 COVID-19 patients distributed across 17 countries.  

By surveying these records, Bourne and Mura found that, indeed, there are statistical trends that track with patient characteristics—chief among these being age, gender and the (age-dependent) usage of estrogen-related hormones (e.g., in post-menopausal women).

“Electronic health records (EHR’s) are a treasure trove of hidden discoveries and more digging is needed, something we at the School of Data Science are intent on,” Bourne said.

The three principal findings of the team’s work were (i) in age-matched strata from about 20-50 yrs old, women have moderately higher rates of COVID-19 infection than men, (ii) in virtually all age ranges, men have higher mortality rates than women, with the effects particularly pronounced beyond age 50 (50% more fatalities among men in their 70s, versus women), and (iii) among post-menopausal women, exceeding age 50, usage of the hormone estradiol tracked with substantially reduced (by over 50%) rates of death.

“The latter point, regarding estradiol, is a key factor that underlies and unifies these observed trends: by considering the microscopic, molecular level—the COVID-related immunological and cellular pathways in which estrogen hormones are likely involved—we can elucidate organism-level disease phenomenon,” notes Mura. 

Bourne went on to add, “these types of studies point to the future of biomedical research - data driven discovery across scales from molecules to populations - true multi-scale modeling.”

In a nutshell, it’s likely that the apparently protective effects of “17β-estradiol”, a naturally occurring, abundant female hormone, relate to a key property of this molecule: it attenuates the “cytokine storm” that’s thought to underlie much of the cellular-scale and organ/tissue-level damage wrought by a SARS-CoV-2 infection, via dysregulation of a patient’s immune response. (SARS-CoV-2, which stands for “severe acute respiratory syndrome, coronavirus 2,” is the technical term for the virus that causes COVID-19.)

Why are men beyond age 50 so much more likely than similarly-aged women to suffer from a severe course of COVID-19, including such a greater likelihood of death? Spurred by such questions, and by the possibility of hormone-related therapies, the international research team undertook a detailed examination of EHRs in light of (i) gender, (ii) systematically varying age strata (from 15 yrs old to age 85+), (iii) in pre- and post-menopausal patient groups, and (iv) in female cohorts that either did or did not use any form of exogenous estrogen-related hormone (e.g., contraception among pre-menopausal adult women, or as part of hormone therapy for post-menopausal cohorts). 

Hormone therapy was found to have a strong linkage to the severity and fatality of COVID-19 among women over age 50.

In terms of new therapeutic avenues, Bourne, Mura and colleagues note that “A chief finding of [our] study is the strong positive effect of... estradiol hormone therapy on the survival rates of post-menopausal women”, and that “whether it could be an effective therapeutic approach not only for women but also for men with COVID-19… is a topic for further research.”  

A preprint of this work, which was recently accepted for publication in BMC Medicine, is freely available at the medRχiv.