Low Testosterone Could Be Bad News in COVID-19

Testosterone levels may be indicative of COVID-19 severity, according to a new study.

In a small, single-center analysis, men with lower testosterone levels were more likely to have a severe case of COVID-19 compared with those with higher levels, Sandeep Dhindsa, MD, of St. Louis University School of Medicine in Missouri, and colleagues reported in JAMA Network Open.

Compared with 24 men who had mild cases of COVID-19, the 66 men with severe illness had significantly lower testosterone levels at the time of diagnosis: 151 ng/dL versus 53 ng/dL, respectively (P=0.01).

This association held true throughout the course of illness. By the third day of COVID infection, those with a severe case had average testosterone levels of 19 ng/dL versus 111 ng/dL in men with mild cases (P=0.006).

On the whole, serum testosterone levels generally decreased during hospital stay, reaching their lowest point around the third day of hospitalization, but returned to baseline levels by day 28, the researchers reported.

During the time of admission, median testosterone concentrations were 65% lower among men with severe illness compared with those with mild COVID-19 cases. By day 3 and 7, testosterone concentrations were 83% and 84% lower in men with severe illness versus those with mild cases. This association was independent of other known COVID-19 risk factors, including age, body mass index, comorbidities, smoking status, and race, the team said.

"During the pandemic, there has been a prevailing notion that testosterone is bad," explained co-author Abhinav Diwan, MD, of Washington University School of Medicine in St. Louis, in a statement. "But we found the opposite in men. If a man had low testosterone when he first came to the hospital, his risk of having severe COVID-19 -- meaning his risk of requiring intensive care or dying -- was much higher compared with men who had more circulating testosterone. And if testosterone levels dropped further during hospitalization, the risk increased."

"The groups of men who were getting sicker were known to have lower testosterone across the board," added Dhindsa in the same news release.

"We also found that those men with COVID-19 who were not severely ill initially, but had low testosterone levels, were likely to need intensive care or intubation over the next two or three days," he said. "Lower testosterone levels seemed to predict which patients were likely to become very ill over the next few days."

Interestingly, testosterone levels in men with COVID-19 were inversely tied to other hormone concentrations. Specifically, those with higher levels of testosterone saw significantly lower levels of interleukin (IL)-6, C-reactive protein (CRP), IL 1 receptor antagonist, hepatocyte growth factor, and interferon γ-inducible protein 10:

• IL-6: β= -0.43 (95% CI -0.52 to -0.17)

• CRP: β= -0.38 (95% CI -0.78 to -0.16)

• IL 1 receptor antagonist: β= -0.29 (95% CI -0.64 to -0.06)

• Hepatocyte growth factor: β= -0.46 (95% CI -0.69 to -0.25)

• Interferon γ–inducible protein 10: β= -0.32 (95% CI -0.62 to -0.10)

On the other hand, concentrations of insulin-like growth factor 1 (IGF-1) and estradiol levels were not tied to COVID-19 severity in men.

There were no significant links between testosterone, estradiol, or IGF-1 concentrations with COVID-19 severity seen in women.

For this prospective cohort study, the researchers drew data on 152 patients who presented to Barnes Jewish Hospital in St. Louis with COVID-19 from March to May 2020. This included 90 men and 62 women (mean age 63), 94% of whom were hospitalized for a median of 3 days with COVID-19. Some of the most common symptoms among these patients were shortness of breath, fever, and a nonproductive cough.

Among the 142 patients hospitalized, 37 died (24%).

Looking just at the 84 men hospitalized, 66 had a severe case of COVID-19, which was defined as hypoxia requiring supplemental oxygen, need for mechanical ventilation, need for intensive care unit treatment, or death due to COVID-19 at any point during hospitalization. These men also tended to be older (age 68 vs 55) and to have more comorbidities (median Charlson Comorbidity Index score 3 vs 2). About half of men with a severe case presented to the hospital with severe illness, while the other half developed severe disease within a median of 2 days into their hospital stay.

Among the men with severe COVID-19, 25 (38%) died.

One limitation of the study, the researchers said, was an inability to assess specifically for free or bioavailable testosterone concentrations, as only total testosterone concentrations were measured. "However, given the three-fold to four-fold difference in total testosterone concentrations between men with and without severe COVID-19, it is extremely likely that free testosterone concentrations would also be lower in men with severe COVID-19," the investigators noted.

Diwan added that they are now looking into a possible association between sex hormones and cardiovascular outcomes in long-hauler COVID-19.

"We also are interested in whether men recovering from COVID-19, including those with long COVID-19, may benefit from testosterone therapy," he said. "This therapy has been used in men with low levels of sex hormones, so it may be worth investigating whether a similar approach can help male COVID-19 survivors with their rehabilitation."

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