Men have a higher mortality rate than women from COVID-19, studies from different countries have consistently shown. Moreover, men remain infectious for longer than women, other studies have amply demonstrated. But why are men more at risk?
Because men were slower to clear the virus from their bodies than women. That may be because the virus could be hiding in their testicles, suggests a new study co-written by researchers of the Albert Einstein College of Medicine in New York and the Kasturba Hospital for Infectious Diseases in Mumbai, India. The paper, published in MedRxiv, has not been peer-reviewed yet.
Not every country has kept statistics on male/female deaths from COVID-19, the disease caused by the SARS-CoV-2 virus, known to humankind since about November 2019. But among those that have, including Italy and China, the death rate for males is roughly double or more than that of females. In Wuhan, the original epicenter of the virus, men accounted for almost 73 percent of the deaths ascribed to COVID-19. (By the way, COVID-19 means “coronavirus disease 2019,” and not the 19th coronavirus we know).
Various explanations have been suggested for the higher mortality rate of men. One proposes that men are more prone to risk-taking behavior, so they are more likely to indulge in counter-survivalist activities, such as smoking and (in the age of coronavirus) group gatherings. But a Chinese study suggests that the answer does not lie in the demon tobacco: Half of Chinese men smoke but smokers comprised only somewhere between 1.4 to 12.6 percent of the male deaths, and similar results were found in New York, according to Forbes.
Another suggestion is that women have generally stronger and more efficient immune systems than men, which on the downside renders women more prone to auto-immune disease.
All this could be spot-on and contribute to the higher male mortality rate from COVID-19. But it wouldn’t explain why men clear SARS-CoV-2 from their bodies more slowly than women.
Checking 68 symptomatic subjects, 40 men and 20 women, the joint American-Indian paper found an average of a two-day delay for symptomatic males to produce “clean” swab-test results compared with symptomatic females.
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“Furthermore, examination of 3 families with both male and female patients followed serially, demonstrated that female members of the same household cleared the SARS-CoV-2 infection earlier in each family,” the team wrote.
Where the coronavirus docks
How might the testicles be involved? To infect a cell, a coronavirus has to “dock” onto a specific protein on the target cell wall, called an ACE2 receptor – which stands for angiotensin-converting enzyme 2. Cell types with copious levels of ACE2 on their surfaces would theoretically be most susceptible to infection. Which cells copiously produce ACE2 receptor proteins? Lungs and kidneys (the renal proximal tubule; COVID-19 is also associated with kidney trouble in severe cases) – and certain testicular tissue.
Specifically, a separate paper published in Nature on Monday detailed that ACE2 is highly expressed in the seminiferous ducts of testis, adult Leydig cells (which produce hormones and are adjacent to those ducts) and in the prostate.
In the kidneys, the receptor is highly expressed in the epithelial cells of the renal tubule, which probably explains why some people with severe cases of COVID-19 have been developing kidney damage.
Conversely, ovaries do not express much ACE2, the Bronx-Mumbai study explains.
So it seems plausible that men are clearing the virus more slowly than women because they have an extra reservoir that women do not possess. It must be stressed that this has not been proven. But it is consistent with this hypothesis that gonadal loss-of-function has been reported in SARS-CoV-2 patients, indicating damage to testicular cells – especially the ones producing hormones – during infection.
On exactly the same grounds – testicular and nephritic susceptibility to coronavirus – a comment published in Nature Reviews, Urology this week urges monitoring the urogenital tract of COVID-19 patients.
“Most patients with severe COVID-19 present with pneumonia-related symptoms, but some patients with severe disease could develop serious urinary complications including acute kidney injury,” writes Shangqian Wang, Xiang Zhou, Tongtong Zhang and Zengjun Wang from the First Affiliated Hospital of Nanjing Medical University.
“Furthermore, male reproductive systems are vulnerable to infection; dramatic changes in sex hormones in patients with COVID-19 have been observed, suggesting gonadal function impairment,” the team writes. Which is a euphemism for infertility.
The changes in the sex hormones are a side effect of inflammation resulting from the immune system fighting the virus, the paper explains: “Inflammatory cytokines that are locally or systematically produced by these cells can activate the autoimmune response, destroying the seminiferous epithelium, which leads to autoimmune orchitis [inflammation of the testicles].”
The team notes that SARS, a different coronavirus, could and did attack the testicles, inducing orchitis. The SARS virus was discovered in the outer cells of testicular seminiferous tubules and Leydig cells, which produce testosterone.
Now, SARS-CoV-2 isn’t the same as SARS-CoV. But both viruses have receptors in the testicles. So while COVID-19 chiefly attacks the respiratory system, doctors should watch out for urogenital complications, the team urges.
They also have a sobering word of advice for men who contracted COVID-19, recovered, and want children: “After recovery from COVID-19, young men who are interested in having children should receive a consultation regarding their fertility.”
This seems to be one thing that China already knew. As early as mid-March, China Daily was warning men who recovered from COVID-19 to have their fertility tested. (It’s worth mentioning that a steady diet of junk food or keeping a smartphone next to boys may have similar effects.)
The authors of the study published in MedRxiv are Aditi Shastri, Justin Wheat, Kith Pradhan, Mendel Goldfinger, Noah Kornblum, Ulrich Steidl, and Amit Verma from the Albert Einstein College of Medicine with Sachee Agrawal, Nirjhar Chaterjee and Aditi’s mother Jayanthi Shastri from the Kasturba Hospital for Infectious Diseases in Mumbai.