Can you have too much of a good thing? The relationship between testosterone and COVID-19 mortality in men

Cinislioglu et al., 2022. The relationship of serum testosterone levels with the clinical course and prognosis of COVID‐19 disease in male patients: A prospective study. Andrology

In the early stages of the COVID-19 pandemic, when it became apparent that disease severity was worse for men than women, attention quickly focused on the potential role of testosterone in mediating disease severity.

Many people speculated that testosterone may be affecting immune system function or entry of the SARS-CoV-2 virus into cells (via effects on angiotensin-converting-enzyme-2; ACE2) to worsen disease in men, but such effects remain unproven.

The rapid appearance of COVID-19, and accelerated publishing of related scientific and medical literature, resulted in trials of treatments based on such theories and hypotheses without supportive fundamental data.

Until recently, it was not known how variations in men’s testosterone levels were related to COVID-19 outcomes.

Inhibition of the hypothalamic-pituitary-gonadal axis is characteristic of acute illness. Accordingly, testosterone levels in men with COVID-19 are lower in men with more severe illness than in those with milder disease^[1]. These observations, though, are confounded by the acute illness. Is COVID-19 severity worse because testosterone levels are low, or are the lower testosterone levels a consequence of the more severe disease?

To clarify the role of testosterone on COVID-19 outcomes in men, Yeap and colleagues assessed COVID-19 mortality in over 150,000 middle-aged men who had provided serum samples more than a decade ago, to the UK Biobank^[2]. Participants’ serum testosterone levels do not seem to change appreciably as they age^[3], so levels measured in the UK Biobank samples likely reflect men’s circulating testosterone concentrations heading into the pandemic.

In contrast to the relationship between testosterone levels in male patients with COVID-19 and the severity of their disease, low testosterone concentrations in samples taken before their infection by SARS-CoV-2 were not associated with death from COVID-19, after adjustment for a range of sociodemographic, lifestyle and medical factors^[4]. Rather, males with testosterone levels in the highest quintile were more likely to die from COVID-19 than men with testosterone levels in the 3rd and 4th quartiles.

So, what is it about having a high testosterone concentration that might make COVID-19 worse? We don’t know.

Yeap and colleagues speculate about possible biological mechanisms that might underly their observations, but the truth is we do not know enough about COVID-19 – or men’s biology – to fully understand this phenomenon. They suggest an application of their work might be to caution men with relatively high testosterone levels of their elevated risk of death from COVID-19 so that they might take precautions to protect themselves.

The advice to men with high testosterone levels that they should act with caution might fall on deaf ears. Testosterone levels are associated with risk-taking behaviour^[5]. Men with high circulating testosterone concentrations might be the least likely to heed cautionary health advice.

The observations of Yeap and colleagues might be more relevant in the context of recent trends of using medications and red lights for ‘testosterone boosting’^[6]. For all its purported benefits, having a high testosterone level might not be such a good thing after all.

Perhaps you can have too much of a good thing.