Androgen Influence on COVID-19 Outcomes

Men develop more severe COVID-19 than women in most settings, a disparity linked to androgen regulation of key viral entry factors and immune modulation. Androgens bind the androgen receptor (AR) to upregulate transmembrane serine protease 2 (TMPRSS2), which primes the SARS-CoV-2 spike protein, and may also influence expression of angiotensin-converting enzyme 2 (ACE2). Variations in AR sensitivity, circulating testosterone and downstream metabolites such as estradiol affect viral uptake, inflammatory responses and tissue injury. Antiandrogen therapies—including AR antagonists and androgen deprivation—have been explored to reduce TMPRSS2 and ACE2 levels, dampen pro-inflammatory cytokine release and mitigate lung damage. Biomarkers such as TMPRSS2, aromatase and testosterone levels correlate with disease severity and mortality. Ongoing clinical trials address the therapeutic potential of AR blockade and refine prognostic algorithms for patient stratification.

Research from Nature Portfolio

Recent studies have delineated sex differences in pulmonary expression of entry factors. Analyses in human and murine lungs revealed no male-biased increase in TMPRSS2 but confirmed higher AR and ACE2 levels in males, with modest suppression of ACE2 by AR antagonism. Organ-specific binding of AR was shown to govern TMPRSS2 regulation: AR inhibitors reduced TMPRSS2 in prostate but not in lung epithelium due to distinct enhancer usage. Complementary work demonstrated that treatment with an AR antagonist significantly lowered TMPRSS2 expression and reduced SARS-CoV-2 entry in human lung cells, supported by co-expression analyses in target cell subsets. Together, these findings clarify that sex-discordant COVID-19 outcomes arise from differential ACE2 regulation and that lung-specific TMPRSS2 expression is largely AR-independent.

Androgen Influence on COVID-19 Outcomes publication trend

The graph below shows the total number of articles in androgen influence on covid-19 outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Androgen receptor (AR): A nuclear transcription factor activated by androgens that regulates genes including TMPRSS2.

TMPRSS2: A cell-surface serine protease that cleaves the SARS-CoV-2 spike protein to facilitate viral entry.

ACE2: The host cell receptor for SARS-CoV-2 spike protein, critical for viral attachment and uptake.

Antiandrogen: A drug that inhibits androgen effects by blocking AR binding or reducing androgen production.

Cytokine: A signalling protein released by immune cells that mediates inflammation and host defence.

References

1. Sex differences in COVID-19: the role of androgens in disease severity and progression. Endocrine (2020).
2. Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes. Scientific Reports (2021).
3. Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. Nature Communications (2021).
4. The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells. Nature Communications (2021).
5. Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response. Proceedings of the National Academy of Sciences of the United States of America (2023).
6. Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells. International Journal of Molecular Sciences (2023).
7. Aromatase, testosterone, TMPRSS2: determinants of COVID-19 severity. Biology of Sex Differences (2024).