Low Testosterone Linked to Worse COVID Outcome

By Megan Brooks

July 09, 2021

NEW YORK (Reuters Health) - Hypogonadism present at hospital admission for COVID-19 is independently associated with poor outcome, finds a new study from Italy.

"Over the first COVID-19 wave, there was a huge difference between men and women presenting to the emergency department because of symptomatic SARS-CoV-2 infection, with more severe clinical outcomes for males compared to females," Dr. Andrea Salonia of San Raffaele University Hospital, in Milan, told Reuters Health by email.

Reasons for gender disparity in COVID severity are unclear but circulating androgens could be a factor.

To investigate further, Dr. Salonia and colleagues compared 286 male COVID-19 patients seen in the emergency department with 305 healthy male controls who were negative for SARS-CoV-2 or SARS-CoV-2-positive but asymptomatic and unaware of their infection status.

Total testosterone (TT) levels were significantly lower in patients with symptomatic COVID-19 compared with healthy controls (mean, 2.5 nmol/L vs. 10.4 nmol/L) and asymptomatic/unaware controls (mean, 11.8 nmol/L), the researchers reported at the virtual European Association of Urology Congress (EAU21).

At hospital admission, hypogonadism (TT < 9.2 nmol/L) was observed in 257 (89.8%) patients with COVID-19, versus 42 (14.9%) healthy controls and nine (33%) asymptomatic/unaware controls (P<0.0001).

COVID-19 patients who were admitted to the intensive-care unit (ICU) or died of COVID-19 had lower TT levels (1.0 and 0.7 nmol/L, respectively) compared with patients with mild COVID-19 or COVID-19 patients admitted to the hospital's internal medicine unit (3.9 and 3.0 nmol/L, respectively; P<0.0001).

On logistic regression analysis, a lower TT level was associated with a higher risk of death (odds ratio, 0.66; 95% confidence interval, 0.45 to 0.98) after accounting for the critical illness score.

"The relationship is very clear: the lower the testosterone, the higher the severity of the condition and likelihood of death," Dr. Salonia said in a conference statement.

Because the researchers did not have data on testosterone levels before the COVID-19 diagnosis, they can't say whether low testosterone was a pre-existing long-term condition that exacerbated the disease or whether it was related to the virus.

"We simply don't have the data to know which came first in these patients, the low testosterone levels or the COVID," Dr. Salonia said in the statement.

However, other research has shown that some receptors for the virus, including the enzyme TMPRSS2, are linked to male hormones and that the virus reduces the number of testosterone-producing Leydig cells.

"Testosterone does play a role in protecting men from disease. However, it's also possible that the virus itself is able to induce an acute reduction in testosterone levels, which then predisposes these men to a worse outcome. We're now following up these patients over a longer time period, to see how their hormone levels change over time, so we can try and answer these questions," Dr. Salonia said.

Dr. Dimple Chakravarty, assistant professor of urology at Icahn School of Medicine at Mount Sinai, in New York City, told Reuters Health by email, "When it comes to the pathogenesis of COVID-19 and morbidity, the role of testosterone should be considered as a double-edged sword."

"Testosterone is required for expression of ACE2 and TMPRSS2 via the androgen-receptor signaling, and testosterone has immunosuppressive functions. Hence one would expect that testosterone should be high in men with COVID-19," said Dr. Chakravarty, who was not involved in the new research.

However, androgen-reducing medications have recently been shown to improve COVID-19 outcomes (https://go.nature.com/2SSfrzJ).

"Is it that reduction in testosterone levels is the body's mechanism to fight virus? This study elucidates a paradoxical role for testosterone and is an important study that opens up few very interesting hypotheses," Dr. Chakravarty said.

In a conference statement, EAU member Dr. Jens Sonksen agrees that there is "much still to learn" about SARS-CoV-2 and its possible health consequences.

"This is highlighted by this new research, which found a surprisingly low level of total testosterone in men with COVID-19 compared to healthy controls. Symptomatic COVID-19 patients with low testosterone were also more likely to become critically ill from COVID-19. Additional research on potential impacts from COVID-19 on men's health is definitely needed," said Dr. Sonksen.

SOURCE: https://bit.ly/3wgM6MZ European Association of Urology Congress (EAU21), held July 8 to 12, 2021.