Do androgens play a role in COVID-19 severity?

As of April 5, 2022, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19), has infected over 493 million and caused over 6.15 million deaths worldwide.

Study: Androgen receptor polyQ alleles and COVID-19 severity in men: a replication study. Image Credit: kostasgr / Shutterstock.com

Sex-related differences in COVID-19

Several studies have suggested a sex-related difference in the severity of COVID-19 that contributed to less favorable outcomes in men. However, age, lifestyle factors, comorbidities, and infection rates are not able to explain these sex-related differences in disease outcomes.

Thus, some researchers have proposed that genetics likely contributes to these sex-based differences, as many X-linked genes are known to be involved in the immune response. For example, several recent studies have indicated an association between the polyQ polymorphism within exon 1 in the androgen receptor (AR) Xq12 gene and COVID-19 severity.

This genetic mutation consists of a polymorphic CAG repeat segment that is located at the N-terminal transactivation domain. The presence of 23 or more CAG repeats has been associated with more severe COVID-19 outcomes in an initial cohort of Italian men and women, as well as an independent cohort of Spanish males.

The response to androgen hormones is mediated by AR which, upon binding to androgen, moves to the nucleus and regulates the expression of the androgen-responsive genes. Previous studies have indicated that lower testosterone concentrations are associated with higher severity and mortality in males with COVID-19.

The expression of the transmembrane serine protease 2 (TMPRSS2), which is a protease that cleaves the SARS-CoV-2 spike protein, is regulated by the androgen response. Furthermore, the transactivational activity of AR has been reported to be regulated by the polyQ polymorphism.

A new study published on the preprint server medRxiv* assesses the association between the AR polyQ polymorphism with COVID-19 severity using a large cohort of 1,136 COVID-19 male patients.

About the study

The current study included 1,136 male patients who were recruited from four hospitals in Spain and were infected by SARS-CoV-2, as indicated by positive reverse-transcription polymerase chain reaction (RT-PCR). All study participants were enrolled retrospectively and prospectively into the study from March 2020 to November 2020 and were followed up until February 2021.

Clinical information which included demographic data, COVID-19 symptoms, related complications from COVID-19, comorbidities, laboratory findings, intensive care unit (ICU) admission, treatments, and outcomes were collected from electronic medical records. The patients were then stratified using three criteria including asymptomatic, oligosymptomatic, or patients with mild symptoms who did not require hospitalization, hospitalized patients who did not require invasive or non-invasive mechanical ventilation, or patients with severe SAR-CoV-2 infection who were admitted to hospital and required intubation, non-invasive ventilation, or high-flow nasal cannula.

Genomic DNA isolated from collected blood samples was used to determine the number of CAG repeats (polyQ polymorphisms) at the AR. Accordingly, patients were classified into short (<23 repeats) or long (≥23 repeats) allele carriers.

The ancestry of each patient was determined with the help of principal component analysis (PCA). This allowed for the patients' ethnicity to be classified as European, admixed American, African, or East Asian.

Study findings

The average age of the patients was about 61 years, a majority of whom were of European origin. The two frequent comorbidities reported among the patients were hypertension and obesity. A total of 15.5% of patients were oligosymptomatic, 21.3% experienced severe COVID-19, and 63.2% required hospitalization without any respiratory support.

The mean number of polyQ CAG repeats was 22. The distribution of both short and long alleles did not show any significant difference between severity classes.

Moreover, the distribution of longer polyQ alleles was similar among more severe patients and milder cases. No significant difference in the distribution of the longer allele was observed with age. Furthermore, patients of European ancestry were similar to the entire study population.

The researchers also reported that factors such as age, ethnicity, obesity, and enrollment centers were associated with COVID-19 severity; however, longer polyQ alleles were not associated.

Taken together, the current study determined that the value of the polyQ polymorphism in the AR gene did not serve as a severity biomarker of COVID-19. Further research is required to understand the association between androgens and COVID-19 severity.

*Important notice

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.

Written by

Suchandrima Bhowmik

Suchandrima has a Bachelor of Science (B.Sc.) degree in Microbiology and a Master of Science (M.Sc.) degree in Microbiology from the University of Calcutta, India. The study of health and diseases was always very important to her. In addition to Microbiology, she also gained extensive knowledge in Biochemistry, Immunology, Medical Microbiology, Metabolism, and Biotechnology as part of her master's degree.