When the H7N9 strain of avian influenza A virus hit East China in 2013, early studies reported that men were more prone to severe and fatal illness following infection with this strain (1). The observation intrigued influenza virologist Gülsah Gabriel from the Leibniz Institute of Virology. She and her colleagues spent a decade unraveling this phenomenon. They found that this respiratory infection leads to an inflammatory cytokine response in the testes and lowers circulating testosterone levels, linking these alterations to worse outcomes in mouse models (2). 

As SARS-CoV-2 infections emerged at the onset of the pandemic, it became evident that once again, severe disease disproportionately affected men compared to women (3). “Of course, we did have déjà vu,” said Gabriel. 

It is one of the first studies [showing] that the lung, which is not a classical or typical endocrine organ, suddenly can become an endocrine organ upon infection. 
- Gülsah Gabriel, Leibniz Institute of Virology

Through an extensive analysis of a large human COVID-19 cohort, human autopsy-derived lungs, and experiments in the golden hamster animal model, Gabriel and her colleagues identified a key player that contributes to severe COVID-19 outcomes in men: the CYP19A1 gene, which encodes a testosterone-to-estradiol metabolizing enzyme called aromatase. The study describing these findings, published in Cell Reports Medicine, suggests promising avenues for developing novel therapeutic strategies to treat SARS-CoV-2 infections in men (4).

Similar to people infected with H7N9, men with severe COVID-19 have reduced testosterone levels (5). To reveal the origins of this decline, Gabriel and her colleagues searched for polymorphisms in four genes key to testosterone metabolism. The team analyzed data from 2,866 patients infected with SARS-CoV-2, and they found that the mutation that most strongly associated with COVID-19 was located within the CYP19A1  gene. Previous studies suggested that this mutation increases the enzyme’s activity, leading to reduced testosterone levels and elevated estradiol levels (6). According to Gabriel’s analysis, approximately 68.7 percent of all men hospitalized for COVID-19 harbor this mutation, which is otherwise rare in the general population. This suggests that men carrying it are at a higher risk for severe illness upon infection. 

Gabriel’s team also found that regardless of the mutation, SARS-CoV-2 infection increases the expression of aromatase. For instance, lung cell cultures infected with this virus had approximately 40 times higher mRNA expression from this gene than cells infected with another coronavirus, SARS-CoV, or H1N1 influenza virus. Lung tissue from men who died of COVID-19 had also higher mRNA and protein levels of the enzyme compared to those dying for other reasons. 

Experiments in golden hamsters confirmed the link between aromatase and SARS-CoV-2 infections. The expression of CYP19A1 significantly increased in the lungs of virus-infected male hamsters, leading to decreased testosterone and higher estradiol levels in the plasma of the animals. 

“It is one of the first studies [showing] that the lung, which is not a classical or typical endocrine organ, suddenly can become an endocrine organ upon infection,” said Gabriel. “It seems that [respiratory viruses] can have long-lasting effects if they dysregulate the enzymes.” 

Gabriel and her colleagues then tested whether targeting this enzyme could improve disease outcomes in the hamsters. To do so, they administered oral letrozole, an aromatase inhibitor. In SARS-CoV-2 infected male hamsters that received this drug, estradiol levels decreased significantly. Testosterone levels increased, though not by a statistically significant amount. The researchers hypothesized that the presence of the virus in the testes, which probably inhibited sex hormone production, prevented any additional surge in testosterone levels. Yet, the partial hormonal balance restoration led to notable improvements in lung health in male hamsters following infection.

Patricia Silveyra, a respiratory physiologist at Indiana University Bloomington who did not participate in this study, said that it was very well conducted. She highlighted that the findings may help identify men at risk for severe COVID-19. Checking if this enzyme is mutated in a patient could better inform the treatment. 

While the drug letrozole is clinically approved to treat breast cancer in women and hypogonadism in men, Silveyra cautioned that its translation to humans for treating severe COVID-19 requires further analysis since multiple tissues express this enzyme. “If you give a systemic treatment [targeting the] aromatase, you may be affecting other parts of your health that may benefit from having their aromatase working,” she said. “The animal model is the first step to identify this mechanism, and then there has to be more preclinical work to detect where it is happening.”

Looking back, Gabriel thinks that her previous work with influenza was of great help in understanding this similar phenomenon in COVID-19. “Without that study, clearly we might not have had the idea of going deeper into the hormone metabolism,” she said. Her team’s findings highlight the importance of considering hormones, which are often overlooked in respiratory infections, particularly in preparation for future pandemics.

References

1. Li, Q. et al. Epidemiology of Human Infections with Avian Influenza A(H7N9) Virus in China. N Engl J Med  370, 520-32 (2014). 
2. Bai, T. et al. H7N9 avian influenza virus infection in men is associated with testosterone depletion. Nat Commun  13, 6936 (2022).
3.  Jin, J.-M. et al. Gender Differences in Patients With COVID-19: Focus on Severity and Mortality. Front Public Health  8, 152 (2020). 
4. Stanelle-Bertram, S. et al. CYP19A1 mediates severe SARS-CoV-2 disease outcome in males. Cell Rep Med  4, 101152 (2023).
5. Infante, M. et al. Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19. Eur Rev Med Pharmacol Sci  25, 5889-5903 (2021).
6.  Payne, E.J. et al. In Vitro Kinetic Properties of the Thr201Met Variant of Human Aromatase Gene CYP19A1: Functional Responses to Substrate and Product Inhibition and Enzyme Inhibitors. J Clin Endocrinol Metab  94, 2998-3002 (2009).