1 INTRODUCTION
It is necessary to explore medications for the prevention of severe cases of coronavirus disease 2019 (COVID-19) and for improving patient outcomes, owing to the low rates of uptake for vaccine boosters (for example, only 54.8% and 14.3% of the total population in European Union/ European Economic Area countries received the first and second booster doses, respectively) 1, the waning efficacy of vaccines 2, and the emergence of new variants3. Various medications and treatments for COVID-19, including corticosteroids, immunomodulatory agents, monoclonal antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been investigated 4.
Notably, it has been hypothesized that serum sex hormone concentrations, particularly testosterone levels, and androgen receptor activation may contribute to the immunoregulatory response and higher risks of COVID-19 susceptibility and severity 5-8. Androgen was considered as a potential hormone therapeutic target for COVID-19. However, androgen suppression drugs (e.g., degarelix and enzalutamide) did not significantly improve the COVID-19 outcomes in recent randomized clinical trials (RCTs)9,10. Meanwhile, a recent study provided conflicting evidence that there was an association between lower testosterone levels and severe COVID-19 in men 11. Thus, so far, little evidence has been found to support a protective role of androgen receptor signaling inhibition against COVID-19 12. Furthermore, other RCTs (e.g., NCT04865029, NCT04853069 and NCT04539626 as listed on ClinicalTrials.gov) investigating the efficacy of estradiol and progesterone therapy on the COVID-19 outcomes are still onging without clear conclusions 13,14. Causal relationships between serum sex hormones and COVID-19 susceptibility and severity, particularly potentially sex-specific effects, remain largely unclear.
The present study aimed to systematically investigated the sex-specific causal effects of serum sex hormone levels on COVID-19 outcomes using data from the UK Biobank (UKB) and COVID-19 Host Genetics Initiative (HGI).