A recently published review article highlights sex differences in COVID-19 outcomes and the mechanisms by which testosterone might play a role.1
Summarizing the key messages from the research, Mohit Khera, MD, MBA, MPH, told Urology Times®, “Testosterone has been shown to play a role in modulating the immune response and may have a protective role in men who are infected with COVID-19. Although it is too early to assess the true relationship between COVID-19 and testosterone, early data suggest that low testosterone levels increase the risk of developing severe disease and that testosterone supplementation may provide benefit for men who are infected by the SARS-CoV-2 virus.”
Khera is a professor of urology, Baylor College of Medicine, Houston, Texas. He said he was prompted to investigate a potential relationship between testosterone and COVID-19 outcomes because of growing evidence that men were disproportionately affected by the infection compared to women and suffered a threefold higher mortality rate. In addition, observations from several studies indicated that men with low testosterone levels who acquired COVID-19 were more likely to be admitted to the intensive care unit and had increased mortality.
Discussing mechanisms by which testosterone can affect COVID-19 risk and outcomes, the article suggests that susceptibility to infection and its severity may involve effects of testosterone on viral entry into host cells and fusion of the virus with the host cell membrane. The underlying mechanisms might be explained by effects of testosterone on angiotensin-converting enzyme type 2 and transmembrane protease serine 2, respectively.
The explanation for why men suffer worse disease severity and higher mortality could relate to the potential for testosterone to affect the host’s immune response. In particular, testosterone can modulate production of pro-inflammatory cytokines, increase expression of anti-inflammatory mediators, and directly modulate activity of CD4+ T lymphocytes.
Understanding of how testosterone influences immune regulation suggests a potential role of testosterone as a therapeutic intervention for COVID-19, and perhaps particularly in men with low testosterone levels. Testosterone supplementation may also provide value considering clinical evidence from studies of patients with chronic obstructive pulmonary disease that investigated associations between testosterone and lung function. As reviewed in the published article by Khera and coauthor Jeremy M. Auerbach, BA, studies of patients with COPD found relationships between testosterone levels and respiratory muscle activity, exercise capacity, and respiratory parameters. In addition, findings from a randomized controlled trial showed that testosterone replacement in patients with COPD was associated with improvement in peak oxygen consumption and respiratory function.
“We believe that further research is needed to accurately assess the efficacy of testosterone replacement therapy in patients with COVID-19. Ideally, these studies should stratify patients by age and be designed to examine the ideal timing and dosage of testosterone supplementation,” Khera said.
Although the available evidence shows an association between low testosterone levels and worse severity of COVID-19, Khera cautioned that causality cannot be assumed.
He said, “There is still much unknown in this field. We also know that obesity and metabolic syndrome that are risk factors for hypogonadism are also risk factors for greater disease severity and increased mortality with COVID-19.”
1. Auerbach JM, Khera M. Testosterone's role in COVID-19. J Sex Med. 2021;18(5):843-848. doi:10.1016/j.jsxm.2021.03.004