Men at higher risk for Covid-19: the important role of androgens

Recent studies suggest that androgens, the male sex hormones like testosterone, promote the entry of coronavirus into cells, which may explain why men are more affected by Covid-19 than women.

From the beginning of the Covid-19 pandemic, it was quickly noted that men were much more affected by severe forms of the disease than women. This difference in susceptibility by sex is particularly striking in Lombardy (Italy): the analysis of 1,591 patients admitted to intensive care from February 20 to March 18 revealed that men represented no less than 82% of the patients (1). Men are not only more affected by COVID-19, but they are also at higher risk of dying from complications of the disease: a study carried out in New York has shown that the mortality rate of hospitalized patients was higher in men than in women, in all age groups (2).

Involvement of androgens

The immune system of women is better than that of men and it is likely that this factor contributes to the difference in susceptibility to coronavirus infection observed between the two sexes. On the other hand, recent observations suggest that male sex hormones (androgens) could also play an important role. For example, a study in Spain reported that men with baldness represented a disproportionate fraction of patients hospitalized due to Covid-19: a census of 122 patients hospitalized in 3 establishments in Madrid found that 79% of men treated for the disease were bald, while the normal proportion of baldness for men of the same age is around 40% (3). Another study (41 patients) arrived at similar results, with 71% of the patients who were bald. Since baldness is associated with high levels of dihydrotestosterone, an active metabolite of testosterone, it is therefore possible that androgens increase the risk of coronavirus infection and / or accelerate the development of complications from Covid-19. In fact, analysis of blood androgen levels in patients with Covid-19 has shown that a high amount of androgens is associated with a significant increase in the risk of severe complications of the disease, including cardiac (4).

Prostate cancer

Another indication of the potential role of androgens comes from studies in men with prostate cancer. The growth of this cancer is stimulated by androgens (testosterone and dihydrotestosterone) and a common therapeutic approach is to reduce the levels of these androgens with drugs that block the production of these hormones (LH-RH analogs or antagonists like leuprolide or degarelix, for example). Italian researchers have shown that prostate cancer patients who were treated with these drugs were 4 times less likely to be infected with the coronavirus and develop complications from Covid-19, again suggesting that androgens contribute to the development of this disease (5).

This association between androgens and infection by the coronavirus is biologically plausible: to infect cells, the proteins present on the surface of the coronavirus must be cut by an enzyme called TMPRSS2 present in the cell membrane, which allows the virus to interact with the ACE2 receptor and subsequently enter the cells.

Very interestingly, it has been shown that the expression of TMPRSS2 is strongly stimulated by androgens and that mutations in this enzyme are present in a high proportion of prostate cancers. Reducing androgen levels would therefore decrease the expression of TMPRSS2 on the surface of cells, thereby preventing virus infection. Several clinical trials are underway and are expected to determine the therapeutic potential of the antiandrogenic approach for the treatment of Covid-19 (6).

(1) Grasselli G et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA 2020; 323: 1574-1581.

(2) Richardson S et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020; 323: 2052–2059.

(3) Wambier CG et al. Androgenetic alopecia present in the majority of hospitalized COVID-19 patients – The “Gabrin Sign”. J. Am. Acad. Dermatol., Published May 21, 2020.

(4) Ghazizadeh Z et al. Androgen regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men. bioRxiv, submitted May 12, 2020.

(5) Montopoli M et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Annals Oncol., Published May 6, 2020.

(6) Wadman M. Sex hormones signal why virus hits men harder. Science 2020; 368: 1038-1039.

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