A new paper published in the Journal of Cosmetic Dermatology examines the association between androgens and the coronavirus disease 2019 (COVID-19), as revealed by the research carried out on this topic throughout the pandemic.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, towards the end of 2019 and then spread worldwide. A notable feature of the outbreak was the markedly greater number of infected men who developed progressive disease than women and adults relative to children. Men were more likely to be hospitalized and admitted to the intensive care unit (ICU) than women with the same initial disease severity.
Even after compensating for confounding factors such as cardiovascular disease, smoking, and drinking, which are much more common among men than women in many cultures, this distinction remains noticeable. Moreover, the earlier outbreak of the Middle East respiratory syndrome (MERS), caused by another betacoronavirus, also showed the same difference in disease severity between genders, with the sex hormone variations between sexes being instrumental in the susceptibility to severe disease.
Androgens and COVID-19
Androgens are steroid hormones found in both sexes but at a much higher concentration in males after puberty. Like other steroid sex hormones, they bind to their specific receptors on the nucleus to cause the 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 chromosome locus Xq11–12.
Androgens have also been found to promote the expression of the serine protease TMPRSS2, an enzyme that is key to SARS-CoV-2 infection, by priming the viral spike protein. This protein mediates virus-cell attachment through the host cell receptor, the angiotensin-converting enzyme 2 (ACE2).
Androgen deprivation therapy (ADT), which is used in prostate cancer patients, reduces the expression of TMPRSS2 on the cell membrane. This, in turn, reduces the ability of the virus to infect the host target cell and bind to the ACE2 receptor. In fact, such patients had a lower risk of progressive disease following infection with SARS-CoV-2, while other individuals with androgen-dependent conditions like androgenetic alopecia, with high androgen levels, were more likely to progress to severe disease.
Nonetheless, the connection is not straightforward. For instance, many European countries reported that testosterone levels in ICU COVID-19 patients were actually lower than in the general population. This is noteworthy, even considering the lack of control groups and baseline testosterone levels from the pre-pandemic period.
Age is associated with decreasing testosterone levels, yet advancing age is an established risk factor for severe COVID-19. This can be explained by the fact that severe systemic inflammation is thought to be responsible for severe disease in COVID-19, in addition to age and underlying chronic illness. Such inflammation has been linked to a reduction in testosterone levels.
The inter-individual variability in AR sensitivity due to polymorphisms of the cysteine adenine guanine (CAG) repeat in the N-terminal transactivation domain of the AR gene can also lead to 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 the observed differences in COVID-19 mortality between ethnic groups, such as high mortality among African Americans compared to other groups. This group also has higher rates of aggressive prostate cancer, in keeping with the shorter CAG repeats.
Research is ongoing to assess the impact of this factor on lung tissue.
COVID-19 therapies and androgens
Several drugs postulated or known to be partially effective in treating COVID-19 act via androgen receptors, in some part at least. For instance, androgen production is affected by hydroxychloroquine, a drug promoted as an effective and safe preventative and therapeutic against COVID-19 by several high-profile personalities, scientists, and otherwise.
A similar drug was nitric oxide (NO), the generation of which is lowered by AR inhibition. In turn, NO reduces AR promoter activity, suppressing the expression of both 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. Thus, the observed inhibitory effect of NO on COVID-19 might be attributable to these factors.
Dexamethasone was shown to reduce mortality in COVID-19 patients on mechanical ventilation by a third and in those on oxygen by a fifth. This drug is known to reduce testosterone production, and this mechanism should be examined and validated if present.
Ongoing studies have shown an association between the therapeutic potential of androgen suppressors, such as 5-alpha reductase inhibitors, most of which are easily available and widely used. The value of this approach needs to be confirmed on an urgent basis so that it can be offered to COVID-19 patients.
For instance, men treated with anti-androgens had a much lower rate of ICU admission, at 8%, compared to 56% for other men. Conversely, androgenetic alopecia was associated with a poor prognosis in COVID-19.
What are the implications?
The TMPRSS2 and ACE2 genes are essential for viral entry into the host cells, making them potential therapeutic targets. The expression of the former is also affected by androgen activity. The effects of androgens on COVID-19 severity appear to be partly, at least, mediated by the androgen-dependent increase in TMPRSS2 levels in host cells. This could account for the decreased severity of the disease in females and in prepubescent males.
This raises interest in the role of anti-androgens and androgen receptor antagonists in the treatment and secondary prevention of COVID-19. Moreover, tests of androgen sensitivity could help predict patient outcomes. Much depends on the results of the studies that are currently going forward to establish the true place of androgens and androgen suppression in the pathogenesis and treatment of COVID-19.