There is overwhelming evidence suggesting that the male gender is at higher risk of developing more severe COVID-19 disease and having poorer clinical outcomes. However, the relationship between COVID-19 and testosterone is still not fully understood. A meta-analysis of over three million COVID-19 cases worldwide has shown no sex-based differences in the proportion of cases. Still, male patients have higher odds of requiring Intensive care treatment and death than females. The difference in severity between sexes is apparent across several countries when comparing COVID-19-related fatalities.
There are many theories on why the severity and mortality of COVID-19 increased in men. One idea is that women are at increased risk of developing autoimmune diseases but are more resistant to infections than men. A leading theory lies in the fact that angiotensin-converting enzyme-2 (ACE2) has proven to be the receptor for coronavirus, with men having higher expression levels than women. While ACE2 receptors allow COVID-19 to enter cells, ACE2 has protective effects in the lungs and heart.
Many studies have proposed hypotheses to explain the sex differences, including the role of androgens. However, the results of one meta-analysis do not support the hormone theory, stating that if higher testosterone values were the sole factor responsible for sex differences in COVID-19 outcomes, the association would decrease as patients age. Instead, the study found that the amount of association between COVID-19 outcomes and the male sex did not depend on the age of the patient. The results of multiple other studies showed contrary results. This study suggests that while androgen levels affect the severity and course of COVID-19, numerous factors may be involved.
In a study of 152 patients with COVID-19, including 143 hospitalized patients, testosterone concentrations upon presentation and on day three were lower when patients had more severe disease. In addition, the amount of circulating inflammatory cytokines were lower with increased disease severity.
Researchers found that among men diagnosed with COVID-19, those with low testosterone levels are more likely to become seriously ill and end up hospitalized than men with normal testosterone levels. The study analyzed 723 men who tested positive for COVID-19 before vaccines were available. Results of the study indicate that low testosterone levels are an independent risk factor for COVID-19 hospitalization. Men with low testosterone who developed COVID-19 were 2.4 times more likely to require hospitalization than men with testosterone levels in the normal range.
Testosterone levels in patients with mild COVID-19 were also lower than the normal reference range. Lower testosterone levels were also correlated with longer hospital stays and were an independent predictive factor for the length of hospitalization. Reasons for increased mortality for patients with low testosterone were greater incidence of hyperinflammatory syndrome and acute respiratory failure. Another study found that lower testosterone levels were associated with more severe Acute Respiratory Distress Syndrome in males at hospital admission and with deterioration of the condition after hospital admission.
Testosterone Replacement Therapy May be Protective Against COVID-19
Research indicates that normal testosterone production, or TRT, is protective against severe cases of COVID-19 infection. One study found that when testosterone levels were brought up to normal via TRT, there was a protective effect against COVID-19 hospitalizations. Those patients on TRT who were receiving an insufficient amount of testosterone still had higher hospitalization risks.
Few studies have analyzed COVID-19 clinical outcomes for hypogonadal men on testosterone replacement therapy. In one study of 32 hypogonadal men receiving testosterone during their COVID-19 infection, TRT was not associated with a worse clinical outcome. Patients taking TRT had lower rates of ICU admission and mechanical ventilator utilization than patients not on TRT. Since patients in the TRT group had more comorbidities, it may indicate that their TRT had a protective effect.
While evidence suggests that low testosterone levels in male patients are associated with increased COVID-19 severity and mortality, some studies have suggested low testosterone may be protective against COVID-19 in some situations. Further studies are necessary to understand testosterone's long-term impact on COVID-19 severity, recovery, and mortality.
Increased Testosterone Seems to Improve Recovery From COVID-19 Infection
Testosterone may play a functional role in recovery from COVID-19. This role seems likely, as increased and improved testosterone levels correspond with improved COVID-19 outcomes and reduced signs of inflammation. Increased testosterone corresponded with improved health of patients, leading to better outcomes.
In a study of 121 men with hypogonadism, more than 50% of men who recovered from the disease still had low testosterone levels suggestive of hypogonadism at a seven-month follow-up. In addition, in 10% of subjects, testosterone levels at seven months were lower than at baseline. This study suggests the more comorbid conditions at presentation, the lower the likelihood testosterone levels will recover over time.
Specific Receptors Present on Cell Surfaces Impact the Severity of COVID-19 Infection
According to research, the amount and expression of TMPRSS2 and ACE2 receptors on cell surfaces impact the severity and mortality of COVID-19 infection.
First, the increased severity of COVID-19 is related to the presence of a protein, TMPRSS2, on the surface of the cells of patients. When TMPRSS2 resides on the cell membranes of host cells, it increases the infectivity and severity of COVID-19 infection when high levels of testosterone are present. Large amounts of TMPRSS2 on cell surfaces enable COVID-19 to get close enough to the host cell to infect.
Also, the ACE2 cell receptor on cell surfaces affects COVID-19 infection. In general, the ACE2 receptor enables the COVID-19 virus to enter the body–the coronavirus infection can occur in all cells with ACE2 receptors. These receptors are found in cells of the respiratory, digestive, cardiovascular, and urinary systems. Men have higher plasma ACE2 levels than women, possibly reflecting higher tissue expression of the ACE2 receptor for COVID-19 infections.
However, ACE2 receptors on cell surfaces of the lungs and heart protect against COVID-19 infection–the more ACE2 receptors on cell surfaces, the less severe the COVID-19 infection. Males have more ACE2 receptors on cell surfaces of the lungs and heart than females. Hence, low testosterone is associated with less ACE2 receptor activity and increased COVID-19 severity and mortality.
COVID-19 Effects on the Penis and Testicles
The stress related to COVID-19 leads to lower testosterone levels and increased levels of stress hormones. Usually, testosterone levels will return to baseline after the illness. Still, loss of testosterone might lead to fibrosis of the penile tissue, which is more challenging to treat and may be less reversible.
The coronavirus also seems to affect the testicles. The virus enters cells with the help of a protein prevalent in the testicles. Since the testicles are where testosterone is made, the virus may cause decreased testosterone levels. Lower testosterone levels may cause erectile dysfunction, decreased energy, libido, and muscle mass. In addition, low testosterone could increase the body’s inflammatory response, increasing damage to the blood vessels.
Symptoms of Long Covid and Male Hypogonadism Overlap
Many patients meet the criteria for late-onset hypogonadism (LOH) during and following COVID-19 infection, including Long Covid. In Long Covid, signs, symptoms, and conditions continue or develop after acute COVID-19 infection. Long Covid can continue for weeks, months, or even years and occurs more often in people with severe COVID-19 illness. People can become re-infected with the coronavirus multiple times, and there is a risk of developing Long Covid each time. Symptoms of Long Covid vary and include:
- Tiredness and fatigue.
- Hair loss.
- Difficulty breathing or shortness of breath.
- Chest pain.
- Fast-beating or pounding heart.
- Difficulty concentrating.
- Sleep problems.
- Dizziness upon standing.
- Change in smell or taste.
- Depression or anxiety.
About 50% of young patients after the acute phase of COVID-19 met the criteria for LOH. Many patients tend to develop LOH after the acute phase of COVID-19. One possible underlying condition of LOH is the prolongation of primary hypogonadism, observed in the acute phase of COVID-19.
Many symptoms of LOH and Long Covid are common. Since LOH is commonly present during and after COVID-19 infection, both conditions should be considered and tested in these patients. Physicians need to measure serum-free testosterone in patients with fatigue, anxiety, or signs of anemia during the early stages of COVID-19 infection. The clinical significance of LOH in post-COVID conditions demands further investigation.