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

Abstract

SARS-CoV-2 infection is associated with increased morbidities in men compared to women. Androgens are believed to play an important role in SARS-CoV-2 pathogenesis in men due to the postulated androgen-dependency of ACE2 and TMPRSS2. However, it is yet unclear whether the sex bias is mediated by SARS-CoV-2 infection itself or by other confounding factors. Here, using the golden hamster model, we show that SARS-CoV-2 infection attacks reproductive organs, causes massive dysregulation of sex hormones and induces elevated transcription of the androgen-to-estrogen converting enzyme aromatase CYP19A1 in the lung. In male hamsters, SARS-CoV-2 infection causes severely depleted testosterone and highly elevated estradiol levels. In female hamsters, SARS-CoV-2 infection causes reduced estradiol levels. Hormonal dysregulation in infected animals is followed by severe weight loss compared to control groups treated with poly(I:C) or PBS. Lungs of SARS-CoV-2 infected animals present abundant CYP19A1 expression in the endothelium and in macrophages, particularly in males. Prominent CYP19A1 expression in endothelial cells and macrophages was verified in lung sections of deceased Covid-19 males compared to females. Our results demonstrate that SARS-CoV-2 infection leads to massive dysregulation of sex hormones, which may increase the risk for sex-specific disease outcome particularly in combination with comorbidities. These findings provide insights into the complex metabolic cross talk between SARS-CoV-2 infection and sex hormones.

Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

“…First, we wanted to assess whether SARS-CoV-2 infection mediated alterations in sex hormone levels proposed before in an animal model 4 are also observed in Covid-19 patients and pose a risk factor for severe outcome. Therefore, we recruited male and female Covid-19 patients ( n =50) who were admitted to an intensive care unit ( Table 1 and Table S1 ).…”

“…This hypothesis is strengthened by recent findings in the golden hamster model showing that SARS-CoV-2 replicates in the reproductive system (testes, ovaries and uterus) of male and female animals. As a result, male animals present reduced testosterone and elevated estradiol levels 4 . This is fully in line with our findings in the Covid-19 male cohort, which present reduced testosterone levels combined with elevated estradiol levels.…”

“…This is fully in line with our findings in the Covid-19 male cohort, which present reduced testosterone levels combined with elevated estradiol levels. Whether this is due to increased aromatase CYP19A1 (converts testosterone-to-estradiol) mRNA levels in the lung as suggested in the pre-clinical animal model 4 , is unclear and requires further investigation. Noteworthy, the herein identified reduced testosterone levels were of testicular origin only in 25% of all male Covid-19 cases.…”

“…However, the underlying factors of sex disparity observed in Covid-19 remain unclear yet. We have recently shown using the golden hamster model, that SARS-CoV-2 infection attacks the reproductive organs and causes massive dysregulation of sex hormones in infected male and female animals 4 . In the young and lean golden hamsters without comorbidities, the males had reduced plasma testosterone levels combined with elevated plasma estradiol levels, unlike females who showed reduced plasma estradiol levels upon SARS-CoV-2 infection 4 .…”

“…We have recently shown using the golden hamster model, that SARS-CoV-2 infection attacks the reproductive organs and causes massive dysregulation of sex hormones in infected male and female animals 4 . In the young and lean golden hamsters without comorbidities, the males had reduced plasma testosterone levels combined with elevated plasma estradiol levels, unlike females who showed reduced plasma estradiol levels upon SARS-CoV-2 infection 4 . Thus, we wanted to study whether the observed dysregulation in sex hormones upon SARS-CoV-2 infection is also present in Covid-19 patients and poses a risk factor for disease severity.…”