Testosterone Protects Against Severe Influenza by Reducing the Pro-Inflammatory Cytokine Response in the Murine Lung

Abstract

Influenza A virus pathogenesis may differ between men and women. The 2009 H1N1 influenza pandemic resulted in more documented hospitalizations in women compared to men. In this study, we analyzed the impact of male sex hormones on pandemic 2009 H1N1 influenza A virus disease outcome. In a murine infection model, we could mimic the clinical findings with female mice undergoing severe and even fatal 2009 H1N1 influenza compared to male mice. Treatment of female mice with testosterone could rescue the majority of mice from lethal influenza. Improved disease outcome in testosterone treated female mice upon 2009 H1N1 influenza A virus infection did not affect virus titers in the lung compared to carrier-treated females. However, reduction in IL-1β cytokine expression levels strongly correlated with reduced lung damage and improved influenza disease outcome in female mice upon testosterone treatment. In contrast, influenza disease outcome was not affected between castrated male mice and non-castrated controls. Here, influenza infection resulted in reduction of testosterone expression in male mice. These findings show that testosterone has protective functions on the influenza infection course. However, 2009 H1N1 influenza viruses seem to have evolved yet unknown mechanisms to reduce testosterone expression in males. These data will support future antiviral strategies to treat influenza taking sex-dependent immunopathologies into consideration.

Low testosterone and high cytokine levels correlate with lethal H7N9 infections in men: a retrospective cohort study from 98 H7N9 patients

“…However, our data is in line with data reported in murine models, where infection of healthy male mice with influenza A virus was shown to reduce testosterone levels by independent laboratories[10] [12]. Interestingly, treatment of female and male mice with testosterone protected animals from lethal outcome[10]. However, testosterone treatment of elderly male mice was less effective [20].…”

“…One limitation of this study is that we have no information regarding potential comorbidities in these groups, such as diabetes type II or obesity, which are known to lower testosterone levels in men[16–19]. However, our data is in line with data reported in murine models, where infection of healthy male mice with influenza A virus was shown to reduce testosterone levels by independent laboratories[10] [12]. Interestingly, treatment of female and male mice with testosterone protected animals from lethal outcome[10].…”

“…We have recently shown that H1N1 infection itself reduces testosterone levels in male but not female mice. Conversely, treatment of female mice with testosterone protected the majority of H1N1 infected females from lethal outcome[10]. In line, aged male mice with low testosterone levels were reported to undergo elevated pulmonary inflammation and severe disease upon H1N1 influenza virus infection compared to young male mice[11].…”

SARS-CoV-2 induced CYP19A1 expression in the lung correlates with increased aromatization of testosterone-to-estradiol in male golden hamsters

“…Therefore, we used a 2009 pandemic H1N1 influenza A virus (pH1N1) isolate and an avian H7N9 influenza A virus isolated from a patient. Both, pH1N1 and H7N9 influenza virus infections mediated low testosterone levels upon infection but did not alter estradiol levels in male mice in line with previous reports 12 . Thus, the shift in sex hormones from testosteroneto-estradiol detected seems to be specific for SARS-CoV-2 infection in male animals (Extended Data Figure 4).…”

“…Second, we found that in males unlike in females, systemic reduction of testosterone levels is accompanied by elevated estradiol levels, which might additionally affect endocrine functions of the sex hormones. Control male animals infected with H1N1 and H7N9 influenza A virus presented reduced testosterone levels as shown before but not elevated estradiol levels 12 . This is in line with findings from human cohorts, where H1N1 and H7N9 influenza A virus infection in men correlated with low testosterone but not elevated estradiol levels 30 .…”