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The link between androgens and COVID-19

A new publication in the Journal of Cosmetic Dermatology explores the link between androgens and Coronavirus Disease 2019 (COVID-19), as demonstrated by research on the subject throughout the pandemic.

Study: Androgens and COVID-19.  Credit: 3DJustincase/Shutterstock
Study: Androgens and COVID-19. Credit: 3DJustincase/Shutterstock

introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China in late 2019 and then spread around the world. A notable feature of the outbreak was the significantly larger number of infected men developing progressive disease compared to children, compared to women and adults. Men were more likely to be hospitalized and admitted to the intensive care unit (ICU) than women with the same initial severity of the condition.

Even after compensating for confounding factors such as cardiovascular disease, smoking and alcohol consumption, which in many cultures are much more common in men than in women, this distinction remains recognizable. In addition, the earlier outbreak of Middle East respiratory syndrome (MERS), caused by another betacoronavirus, also showed the same difference in disease severity between sexes, with sex hormone differences between sexes being a key contributor to susceptibility to severe diseases have contributed.

Androgens and COVID-19

Androgens are steroid hormones found in both sexes, but in much higher concentrations in men after puberty. Like other steroid sex hormones, they bind to their specific receptors in the cell nucleus to cause transcription of specific genes. Androgen receptors (ARs) are also called nuclear receptor subfamily 3, group C, member 4 (NR3C4). They are encoded by the AR gene on the chromosomal locus Xq11-12.

Androgens have also been found to promote expression of the serine protease TMPRSS2, an enzyme critical to SARS-CoV-2 infection, by activating the viral spike protein. This protein mediates viral cell attachment via the host cell receptor, angiotensin converting enzyme 2 (ACE2).

Androgen deprivation therapy (ADT), used in patients with prostate cancer, reduces the expression of TMPRSS2 on the cell membrane. This in turn reduces the virus’ ability to infect the host target cell and bind to the ACE2 receptor. In fact, such patients had a lower risk of progressive disease after infection with SARS-CoV-2, while other individuals with androgen-dependent diseases such as androgenetic alopecia with high androgen levels were more likely to progress to severe disease.

Nevertheless, the connection is not easy. For example, many European countries reported that testosterone levels in COVID-19 patients in intensive care units were actually lower than in the general population. This is remarkable, even considering there are no control groups and baseline testosterone levels from before the pandemic.

Age is associated with declining testosterone levels, but advancing age is an established risk factor for severe COVID-19. This can be explained by the fact that, in addition to age and underlying chronic disease, severe systemic inflammation is believed to be responsible for severe disease in COVID-19. Such inflammation has been linked to a reduction in testosterone levels.

Inter-individual variability in AR susceptibility due to cysteine-adenine-guanine (CAG) repeat polymorphisms in the N-terminal transactivation domain of the AR gene may also result in unpredictable susceptibility to severe COVID-19 at low testosterone levels. The shorter the repeat, the higher the AR expression and the greater the risk of prostate cancer.

This may also correlate with higher TMPRSS2 transcription and severe COVID-19. CAG repeat length could also correlate with observed differences in COVID-19 mortality between ethnic groups, such as B. High mortality among African Americans compared to other groups. This group also has higher rates of aggressive prostate cancer, consistent with the shorter CAG repeats.

Research is ongoing to evaluate the effects of this factor on lung tissue.

COVID-19 therapies and androgens

Several drugs thought or known to be partially effective in treating COVID-19 act at least in part through androgen receptors. For example, androgen production is affected by hydroxychloroquine, a drug promoted by several high-profile figures, scientists, and others as an effective and safe preventive and therapeutic agent against COVID-19.

A similar drug was nitric oxide (NO), the formation of which is reduced by AR inhibition. In turn, NO reduces the activity of the AR promoter and represses expression of both the ACE2 and TMPRSS2 genes. This could block the entry of the virus into the host cells.

NO also inhibits viral replication while affecting spike-ACE2 interactions. Therefore, the observed inhibitory effect of NO on COVID-19 could be due to these factors.

Dexamethasone has been shown to reduce mortality by a third in COVID-19 patients on mechanical ventilation and by a fifth in patients on oxygen. This drug is known to reduce testosterone production and this mechanism should be studied and validated if it exists.

Ongoing studies have shown an association between the therapeutic potential of androgen suppressors such as 5-alpha reductase inhibitors, most of which are readily available and widely used. The value of this approach urgently needs to be validated so that it can be offered to COVID-19 patients.

For example, men treated with antiandrogens had a much lower rate of intensive care admissions at 8% compared to 56% for other men. Conversely, androgenetic alopecia in COVID-19 was associated with poor prognosis.

What are the effects?

The TMPRSS2 and ACE2 genes are essential for viral entry into host cells, making them potential therapeutic targets. The expression of the former is also influenced by androgen activity. The effects of androgens on the severity of COVID-19 appear to be mediated, at least in part, through androgen-dependent increases in TMPRSS2 levels in host cells. This could account for the reduced severity of the disease in women and prepubertal men.

This sparks interest in the role of antiandrogens and androgen receptor antagonists in the treatment and secondary prevention of COVID-19. Additionally, androgen sensitivity testing could help predict patient outcomes. Much depends on the results of the studies currently being conducted to determine the true place of androgens and androgen suppression in the pathogenesis and treatment of COVID-19.

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