Sex Hormones May Explain Why Men Are Hit Harder By Covid-19

A patient seen in the intensive care unit for COVID-19 in Thoracic Diseases Hospital of Athens in Greece on November 8, 2020.  Alexandros Michailidis/Shutterestock.com

There is increasing evidence that men are at a higher risk of falling severely sick with Covid-19 and are more likely to die from the infection. Just like a handful of other viral infections, sex hormones may help to explain why.

Ever since the pandemic took hold, scientists have noticed that men are at a higher risk of Covid-19, with explanations ranging from biology to behavior. For example, some early speculation suggested this trend might exist because men are more likely to smoke. However, increasing evidence is showing that sex hormones are likely to be a major factor. 

A new paper has suggested that female reproductive steroids, such as estrogen and progesterone, might play a protective role against Covid-19 through their anti-inflammatory properties and effect on the immune system. Discussing the evidence in the journal Trends in Endocrinology & Metabolism, the researcher says this could explain why men are often harder hit by Covid-19 infections than women. It would also back up reports that show pregnant women are much less likely to die of Covid-19 than other infections. 

The idea came to light when Graziano Pinna, research associate professor in psychiatry at the University of Illinois in Chicago, noticed that a significant number of pregnant women who had no Covid-19 symptoms suddenly had worsening symptoms immediately after having their child. Since giving birth results in a sharp drop of estradiol, progesterone, and allopregnanolone, Pinna looked into whether reproductive steroids might be having some protective effect against Covid-19.

“Hormones that help sustain the pregnancy – like progesterone — are 100 times more concentrated in a pregnancy’s third trimester. Estradiol, allopregnanolone, and progesterone all have important anti-inflammatory functions and are involved in resetting the immune system. This suggests that pregnant women became symptomatic, and some were even admitted to the ICU, after delivering their babies because of the rapid drop in these hormones,” Pinna said in a statement“The correlation was really striking."

It’s well-known that female reproductive steroids, estrogen and progesterone, as well as progesterone's metabolite, allopregnanolone, hold anti-inflammatory properties. In fact, the hormones also help immune cells and stimulate antibody production, which is part of the reason men and women respond differently to many viral infections, including flu, SARS, and MERSIt appears the female sex hormones might also help to ward off severe Covid-19 infections too based on these anti-inflammatory properties and their wider effect on the immune system, such as reshaping the competence of immune cells and sparking antibody production. This new study also highlights evidence that shows reproductive hormones promote lung cell repair after virus infection and even inhibits the ACE2 receptor, the main keyhole which the SARS-CoV-2 virus uses to enter a host cell. 

Perhaps most interestingly, the paper also discusses how female reproductive hormones might help to prevent the notorious “cytokine storm,” in which the immune system overreacts in an attempt to control the infection and releases too many pro-inflammatory cytokines, leading to hyper-inflammation. It’s a well-known complication of Covid-19, most notably seen in men, which can lead to fluid build-up in the lungs, tissue damage, and multiple organ failure. 

“Progesterone and allopregnanolone can block the incredible overreaction of the inflammatory system, repressing it and avoiding the over-expression of pro-inflammatory cytokines,” explained Pinna. 

Pinna concludes the paper by noting clinical trials are underway to assess whether treating men and post-menopausal women with progesterone or estradiol could help reduce symptoms in severe cases of Covid-19.

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