4 DISCUSSION
In this study, to the best of our knowledge, we used data from the
largest GWASs of serum sex hormones and COVID-19 outcomes to date, as
well as the MR analysis technique, to systematically investigate the
potential sex-specific causal associations of serum sex hormones with
COVID-19 susceptibility and severity. Androgen signaling inhibition has
been debated regarding its potential to reduce the susceptibility and
severity of COVID-19 in men; however, accumulating evidence does not
support this potential 12, which is consistent with
the MR analysis results in our study. Interestingly, our results suggest
that serum estradiol and bioavailable testosterone may serve as
potential intervention or therapeutic targets for preventing SARS-CoV-2
infection in women.
The role of sex hormones in modulating COVID-19 susceptibility and
severity has generated intense research interest given that sex-specific
differences in these COVID-19 outcomes have been reported globally31-33. However, inconsistent conclusions have been
drawn from various studies. For testosterone, it has been reported that
lower levels of testosterone are associated with a higher risk of
developing severe COVID-19 disease in men 11,34,35.
Moreover, men who had severe COVID-19 or needed intensive care have
higher total testosterone levels than the mild COVID-19 or the control
groups 36. In contrast, estradiol levels were elevated
in men with severe COVID-19 compared to the controls, but no significant
difference was observed in women with critical COVID-1937.
Interestingly, the findings of a previous MR analysis study did not
support the causal effects of estradiol levels in men and women on
COVID-19 susceptibility and severity 38, where a total
of 10 SNPs were selected to genetically predict the estradiol levels in
both men and women. In our study, we conducted a stringent strategy and
LD clumping procedure for genetic instruments selection. Finally, two
genome-wide significant SNPs (i.e., rs45446698 and rs16991615) for
estradiol levels in women and seven SNPs for estradiol levels in men,
respectively, were used for MR analysis (see eTable 2 for
details). GWAS summary data on binary and continuous estradiol levels
were used in our analysis 18. It is worth noting that
our results suggested a protective effect of estradiol levels in women
on COVID-19 infection. Moreover, suggestive causal effects of elevated
estradiol levels in men on COVID-19 hospitalization and critical illness
were observed. These findings may be explained by previous studies and
animal experiments that show estrogens have anti-inflammatory effects
and can affect immune systems 39-41. Experiments
revealed the suppressive function of 17β-estradiol (E2) on the
production of proinflammatory cytokines by macrophages and monocytes,
and its ability to inhibit chemokines to prevent innate immune cells,
such as neutrophils and monocytes, from concentrating into inflamed
areas 42. Additionally, E2 could stimulate CD4+
T-helper cells to produce anti-inflammatory cytokines and produce
antibodies by affecting B cells 39,42,43.
In addition, the angiotensin-converting enzyme 2 (ACE2 ) and the
transmembrane serine protease 2 (TMPRSS2 ) in the lung have been
well-studied as the entry receptor and for the spike (S) protein priming
of SARS-CoV-2 44. Recently, researchers found that
elevated estradiol levels downregulate the expression of ACE2 andTMPRSS2 messenger ribonucleic acid (mRNA) in lung epithelial
cells 14,45,46. This may support the protective role
of increased estradiol levels on COVID-19 infection and critical illness
revealed in our MR analysis.
Although several ongoing or completed clinical trials are targeting sex
hormone pathways, for example, estrogen therapy (NCT04539626), estradiol
(NCT04853069), estradiol and progesterone therapy (NCT04865029) and
non-steroidal androgen receptor antagonist (NCT04870606), hormone
therapy has not been authorized for COVID-19 treatment. A recent
clinical trial did not support the use of androgen suppression treatment
for improving severe COVID-19 illness and hospitalization in men10. This finding was consistent with our results,
which showed that total and bioavailable testosterone levels in men did
not causally associate with the risk of COVID-19 infection or severe
illness. These results are also supported by previous MR studies38,47. The potential implications of our results for
COVID-19 prevention/ treatment warrant further validation in larger
clinical trials.
There were several limitations in our study. Firstly, due to the lack of
large-scale sex-specific COVID-19 GWAS, we utilized sex-combined GWAS
summary statistics of COVID-19 susceptibility and severity as the
outcomes in the MR analysis. Secondly, the findings in this study were
generated using GWAS data of European ancestry. Therefore, the
conclusions of this study may not be generalizable to populations of
other ancestries. Thirdly, due to the lack of individual data, we were
unable to test the potential non-linear causal associations of serum sex
hormones with COVID-19 susceptibility and severity.
In summary, our MR analysis revealed novel causal associations of serum
estradiol and bioavailable testosterone with SARS-CoV-2 infection in
women but not men, except for a suggestive inverse causal association of
estradiol levels with COVID-19 severity in men. This suggests a
sex-specific causal nature of sex hormones in relation to COVID-19
outcomes and their potential roles as therapeutic targets for preventing
SARS-CoV-2 infection and improving patient outcomes. Further validation
in larger clinical trials is warranted.