Throughout the pandemic, doctors have seen evidence that men with COVID-19 fare worse, on average, than women with the infection. One theory is that hormonal differences between men and women may make men more susceptible to severe disease.
And since men have much more testosterone than women, some scientists have speculated that high levels of testosterone may be to blame.
But a new study from Washington University School of Medicine in St. Louis suggests that, among men, the opposite may be true: that low testosterone levels in the blood are linked to more severe disease.
The study could not prove that low testosterone is a cause of severe COVID-19; low levels could simply serve as a marker of some other causal factors. Still, the researchers urge caution with ongoing clinical trials investigating hormonal therapies that block or lower testosterone or increase estrogen as a treatment for men with COVID-19.
“During the pandemic, there has been a prevailing notion that testosterone is bad,” said senior author Abhinav Diwan, MD, a 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 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 researchers measured several 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 illness. For the 143 patients who were admitted to the hospital, the researchers measured hormone levels again at days 3, 7, 14 and 28, as long as the patients remained hospitalized over these time frames.
In addition to testosterone, the investigators measured levels of 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.
Among women, the researchers found no correlation between levels of any hormone and disease severity. Among 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 hospital admission, 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. By day three, the average testosterone level of the most severely ill men was only 19 nanograms per deciliter.
The lower the levels of testosterone, the more severe the disease. For example, those with the lowest levels of testosterone in the blood were at highest risk of going on a ventilator, needing 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, also are associated with lower testosterone. “The groups of men who were getting sicker were known to have lower testosterone across the board,” said first author Sandeep Dhindsa, MD, an endocrinologist at Saint Louis University.
“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. Lower testosterone levels seemed to predict which patients were likely to become very ill over the next few 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 inside the cells.
In other words, the body may be adapting to less testosterone circulating in the bloodstream by dialing up its ability to detect and use the hormone. The researchers don’t yet know the implications of this adaptation and are calling for more research.
“We are now investigating whether there is an association between sex hormones and cardiovascular outcomes in long COVID-19, when the symptoms linger over many months,” said Diwan, who is a cardiologist.
“We also are interested in whether men recovering from COVID-19, including those with long COVID-19, may 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 with their rehabilitation.”
Sex hormones and COVID-19
Epidemiological evidence suggests similar susceptibility to SARS-CoV-2 in men and women. However, COVID-19 disease severity and mortality are higher in men . A meta-analysis of over 3.1 million global cases reported odds ratios of 2.8 and 1.4 for ICU admission and death in men compared to women .
Similarly, a recent nationwide analysis of 84,000 patients and 434,000 controls in Sweden found that male sex was associated with a 1.6-fold increased risk for non-ICU hospitalization, a threefold increased risk of ICU admission, and 1.7-fold increased risk of mortality after adjustment for confounding factors .
Given the disparities of clinical outcomes between men and women, the impact of biological sex on immune response against COVID-19 infection has become an area of interest
Clinical data suggest that behavioral differences might play a role in the outcome of COVID-19. Higher rates of smoking , various social factors including the compliance to protective measures  could contribute to the increased risk of severe disease in men, as well as a higher number of co-morbid diseases  and a low likelihood to be treated with vitamin D for osteoporosis .
Physiological mechanisms that are likely to play a role in sexual dimorphism of COVID-19 outcome include the entrance of virus to the body and immunological differences. SARS-CoV-2 uses ACE2 and the cell surface TMPRSS2 to enter the cells. Recently, it has been shown that androgens regulate transcription of these two host entry factors of SARS-CoV-2 in lung epithelial cells partly explaining the clinical observation of higher COVID-19 morbidity and mortality in men .
Furthermore, ACE2 is widely distributed throughout the body and higher expression and activity is related to severe COVID-19 . Sex-based differences and regulation of ACE2 in various organs might contribute to different clinical manifestations in men and women.
Women and men differ in their immune response to infection . A recent human study has reported that male patients had higher plasma levels of innate immune cytokines along with more robust induction of nonclassical monocytes. Female patients have significantly more robust T-cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
A poor T-cell response negatively correlates with patients’ age and is associated with worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients have been associated with worse disease progression, but not in male patients . Overall, immune responses against SARS-CoV-2 appear to differ between men and women.
Data from the dermatologic literature suggest that bald men are more prone to COVID-19  as well as that androgenetic alopecia is frequent also in women with COVID-19 . However, one of the more impactful observations in this field came from patients with prostate cancer.
In fact, those patients under androgen deprivation therapy  demonstrated in some studies to be less vulnerable to SARS-CoV-2 infection, as compared to patients who were not androgen deprived .
Most intriguingly, recent double-blind placebo-controlled trials showed that selective androgen receptor modulators accelerates viral clearance and reduce time to clinical remission in male patients without prostate cancer hospitalized with mild to moderate COVID-19 as well as a novel androgen receptor inhibitor did show similar positive effects in both males and females with COVID-19 [132, 133].
Therefore, a note of caution appears reasonable concerning the use of testosterone particularly in the elderly with the so-called late-onset hypogonadism in whom the usefulness of androgen replacement is still debated .
reference link: https://link.springer.com/article/10.1007/s12020-021-02734-w
More information: JAMA Network Open (2021). DOI: 10.1001/jamanetworkopen.2021.11398