There is a clear pattern that men tend to have more severe COVID-19 outcomes than women, and researchers have speculated that differences in sex hormones might explain at least part of this difference. This study set out to measure if—and how—levels of sex hormones (like testosterone and estradiol) linked up with markers of abnormal blood clotting and the severity of illness in people admitted with COVID-19.
Study Design and Methods
Researchers collected data from 186 patients with recently diagnosed, symptomatic COVID-19, focusing on postmenopausal women (over 50 years old) and age-matched men. These patients were divided into two groups based on whether they had moderate or severe COVID-19. There was also a control group of 60 healthy individuals of similar age to provide a baseline for comparison.
Blood samples were tested for:
- Markers of hypercoagulability (a tendency for blood to clot more easily), such as D-Dimer, Tissue Factor Pathway Inhibitor (TFPI), and others.
- Endothelial cell activation (which reflects how blood vessels respond to infection and inflammation).
- Sex hormone levels, including testosterone, estradiol, and progesterone.
- Inflammatory markers like IL-6 and complement proteins (C3a, C5a).
The values for these biomarkers were labeled as high, low, or normal by comparing patient results to the control group average plus or minus two standard deviations.
Key Findings Explained Simply
- Men, particularly those over 50, had lower than normal testosterone and abnormal estradiol levels. Their levels of blood clotting markers were also more often outside normal limits compared to women.
- Markers showing a higher tendency for blood to clot (and signs of blood vessel activation) were strongly associated with more severe COVID-19 across all patients, but especially in older men.
- In female patients, estradiol remained within the normal range but dropped in those who developed more severe illness; however, testosterone and progesterone did not show significant differences from normal in women, regardless of disease severity.
- When men developed severe COVID-19 or acute respiratory distress syndrome (ARDS), their testosterone levels were notably lower, and their estradiol levels were higher (though not significantly different between mild and severe cases).
- A relationship was found between these hormone changes and increased inflammation (IL-6), higher D-Dimer, and greater risk of clotting, especially in men.
Technical, Granular, and Holistic Summary
This study holistically demonstrates that sex hormone disturbances—primarily reduced testosterone and altered estradiol/testosterone ratios—are prominent in males with critical COVID-19. These hormonal changes correlate with markers of hypercoagulability (prolonged lag time, increased peak thrombin, elevated D-Dimer, reduced ETP) and heightened endothelial cell activation/immune response (increased TFPI, low thrombomodulin, elevated IL-6 and C3a). These abnormalities were much more frequent in men, particularly those over 50, compared to women and healthy controls. Notably, in women, estradiol levels decreased only in severe cases, while testosterone and progesterone stayed relatively stable. The combination of low testosterone and high estradiol/testosterone ratios was most predictive of severe COVID-19 in men, with the data suggesting that measurement of these hormones alongside coagulation and inflammatory biomarkers could enhance risk stratification upon a patient's admission for infection.
In conclusion, the study provides compelling evidence that monitoring disturbances in sex hormone levels, especially testosterone and the estradiol/testosterone ratio, along with biomarkers of hypercoagulability and inflammation, can serve as a precise, early risk assessment tool for identifying COVID-19 patients—particularly older men—at higher risk for severe disease progression. This supports integrating hormone analysis into COVID-19 clinical management strategies in hospitalized adults.
.svg)
.avif)