Low Testosterone Means High Risk of Severe COVID-19 for Men

A new study from Washington University School of Medicine in St. Louis suggests that low blood testosterone levels in men are linked to more severe COVID-19. The study contradicts widely held assumptions that higher testosterone may explain why, on average, men develop more severe COVID-19 than women. Credit: Sara Moser

New clues as to why more men than women develop serious disease.

During the pandemic, doctors have seen evidence that men with COVID-19 are doing worse on average than women with the infection. One theory is that hormonal differences between men and women can make men more susceptible to serious illness. And since men have much more testosterone than women, some scientists have speculated that high levels of testosterone could be the cause.

But a new study from Washington University School of Medicine in St. Louis suggests that in men, the opposite may be true: that low blood testosterone levels are linked to more serious disease. The study failed to prove that low testosterone is a cause of severe COVID-19; low levels could simply serve as a marker of some other causative factors. Still, the researchers urge caution with ongoing clinical trials of hormonal therapies that block or lower testosterone or increase estrogen as a treatment for men with COVID-19.

The research was published in JAMA Network Open on May 25, 2021.

“During the pandemic, the idea that testosterone is bad was prevalent,” says senior author Abhinav Diwan, MD, professor of medicine. “But we found the opposite in men. If a man had low testosterone when he first came to the hospital, his risk of severe COVID-19 — meaning his risk of intensive care or death — was much higher compared to men who had more circulating testosterone. And if testosterone levels continued to fall during hospitalization, the risk increased.”

The researchers measured different hormones in blood samples from 90 men and 62 women who came to Barnes-Jewish Hospital with symptoms of COVID-19 and who had confirmed cases of the disease. Of the 143 patients who were hospitalized, the researchers measured hormone levels again on days 3, 7, 14 and 28, as long as the patients remained in the hospital during these time periods. In addition to testosterone, the researchers measured estradiol, a form of estrogen produced by the body, and IGF-1, an important growth hormone that is similar to insulin and plays a role in maintaining muscle mass.

In women, the researchers found no correlation between levels of a hormone and disease severity. In men, only testosterone levels were linked to COVID-19 severity. A blood testosterone level of 250 nanograms per deciliter or less is considered low testosterone in adult men. At hospitalization, men with severe COVID-19 had average testosterone levels of 53 nanograms per deciliter; men with less severe disease had average levels of 151 nanograms per deciliter. On day three, the average testosterone level of the most severely ill men was only 19 nanograms per deciliter.

The lower the testosterone level, the more serious the disease. For example, those with the lowest levels of testosterone in the blood were most at risk of being on a ventilator, requiring intensive care, or dying. Thirty-seven patients – 25 of whom were men – died over the course of the study.

The researchers noted that other factors known to increase the risk of severe COVID-19, including advanced age, obesity and diabetes, are also associated with lower testosterone. “The groups of men who got sicker were known to have lower testosterone across the board,” says first author Sandeep Dhindsa, MD, an endocrinologist at Saint Louis University. “We also found that those men with COVID-19 who were initially not critically ill but had low testosterone levels were likely to require intensive care or intubation for the next two or three days. Lower testosterone levels seemed to predict which patients would become very ill in the coming days.”

In addition, the researchers found that lower testosterone levels in men also correlated with higher levels of inflammation and an increase in the activation of genes that allow the body to carry out the functions of circulating sex hormones in the cells. In other words, the body may be adapting to less testosterone circulating in the bloodstream by ramping up its ability to detect and use the hormone. The researchers are not yet aware of the implications of this adjustment and are calling for more research.

“We are now investigating whether there is a relationship between sex hormones and cardiovascular outcomes in long-term COVID-19, when symptoms persist for many months,” said Diwan, who is a cardiologist. “We are also interested in whether men recovering from COVID-19, including those with long-term COVID-19, could benefit from testosterone therapy. 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 in their rehabilitation.”

Reference: “Association of Circulating Sex Hormones with Inflammation and Disease Severity in Patients with COVID-19” by Sandeep Dhindsa, MD; Nan Zhang, PhD; Michael J. McPhaul, MD; Zengru Wu, PhD; Amit K. Ghoshal, PhD; Emma C. Erlich, BA; Kartik Mani, MD; Gwendalyn J. Randolph, PhD; John R. Edwards, PhD; Philip A. Mudd, MD, PhD and Abhinav Diwan, MD, May 25, 2021, JAMA Network Open.
DOI: 10.1001 / jamanetworkopen.2021.11398

This study leveraged Washington University’s COVID-19 biorepository and was conducted in collaboration with the university’s Institute of Clinical and Translational Sciences (ICTS), which includes Saint Louis University School of Medicine.

This work was supported by the National Institutes of Health (NIH), grant numbers R37 AI049653, P30 DK020579, HL107594, and HL143431; and a grant from The Foundation for Barnes-Jewish Hospital to facilitate data collection from the WU350 cohort that supported these studies. These studies were also supported by the Washington University Institute of Clinical and Translational Sciences, grant number UL1TR002345 of the NIH’s National Center for Advancing Translational Sciences (NCATS).