Coronavirus disease 2019 (COVID-19) is characterized by diverse clinical manifestations, including aggravated inflammatory states and tissue and organ damage leading to death. Several studies have shown that although men and women are equally susceptible to infection, men have a significantly higher risk of severe disease and death. Similar observations were seen in studies of SARS-CoV and the Middle East respiratory syndrome (MERS-CoV) outbreaks.
Other correlates of severe COVID-19 are old age, poverty, and co-morbidities, including obesity, cardiovascular disease, and diabetes. Sexual differences in severity of disease have also been observed in racial and ethnic minority groups that have been disproportionately affected by the COVID-19 pandemic. Despite extensive research on COVID-19 manifestations, a precise knowledge of the molecular and biological mechanisms behind the association of severe disease with the male sex is still lacking.
Since angiotensin-converting enzyme 2 (ACE2), the main cellular receptor for SARS-CoV-2, and TMPRSS2, the major viral fusogenic membrane-associated protease, are transcriptionally regulated by androgens, it could be a reason why men have a higher risk of SARS-CoV-2 infection and more severe disease compared to women.
Growing evidence shows that severe COVID-19 in males is accompanied by low levels of circulating testosterone, which suggests the critical role played by androgens in the prevention of innate and/or adaptive immune dysfunctions that result in the development of severe disease.
A better understanding of the relationship between testosterone levels and disease severity
In a study available on the medRxiv* the preprint server, researchers from Spain showed that testosterone trajectories are very accurate individual predictors of survival in male patients with COVID-19. To better understand the relationship between testosterone levels and disease severity, they studied a group of male and female COVID-19 patients assessing their serum and blood biomarkers in association with outcome of disease.
They performed a longitudinal analysis in a sub-cohort of male COVID-19 patients and found that male patients who recover from the disease eventually reinstate testosterone levels, while those who succumb to COVID-19 do not. Longitudinal measurements of blood levels of androstenedione and luteinizing hormone (LH) suggest an early modest inhibition of the central LH-androgen biosynthesis axis in most patients, followed by full recovery in survivors or peripheral failure in fatal cases.
Moreover, there was evidence to show that failure to address low physiological testosterone levels was linked to impaired T helper differentiation and a decrease in non-classical monocytes. The powerful association of recovery or failure to reinstate testosterone levels with survival or death in male COVID-19 patients indicates a significant role of testosterone levels in COVID-19 immune responses.
Findings suggest a functional role for testosterone beyond being just a biomarker of disease outcome
Several studies have identified prognostic markers that could distinguish severe COVID-19 patients, including male sex, age, diabetes, obesity, or cardiovascular disease, elevated inflammation, lymphopenia, and neutrophilia. However, relatively fewer studies have addressed sexual differences in predictive markers of disease outcome. This comparative analysis of biochemical and hematological parameters revealed that both males and females share biomarkers with the significant predictive power of COVID-19 outcome, including LDH, IL-6, D-dimer, lymphopenia, and neutrophilia. However, the levels of these biomarkers and their predictive power were consistently higher in male COVID-19 patients compared to female COVID-19 patients.
A follow-up study is currently ongoing aimed at expanding the present study in this regard, including longitudinal analyses in women.”
To summarize, the close association between the reinstatement of testosterone levels and survival in male COVID-19 patients, along with a reversal of symptoms of excessive inflammation and immune dysfunction, shows a functional role for testosterone beyond being just a biomarker of disease outcome.
Finally, pre-clinical animal models would be required for a robust experimental demonstration of mechanistic relationships between testosterone status (e. g., deprivation and replacement) and SARS-CoV-2 infection outcomes, which should also contemplate factors such as age.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.