In an article recently published in Trends in Endocrinology & Metabolism, Graziano Pinna from the University of Illinois in Chicago outlines some of the evidence suggesting that female reproductive hormones may play a role in the sex bias that has been observed in coronavirus disease 2019 (COVID-19).
Reports have shown that severe COVID-19 symptoms and mortality following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occur more frequently among men than women, suggesting that female reproductive hormones may play a protective role.
Now, Pinna has described some of the effects that estrogen and progesterone have on the immune system that may help to prevent severe symptoms and death as a result of COVID-19.
Pinna provides examples of how the hormones exert anti-inflammatory actions, reshape the competence of immune cells and stimulate higher levels of antibodies against viruses.
He is now calling for clinical trials to investigate whether these hormones could be beneficial to men and postmenopausal women who are at risk of developing severe COVID-19.
The hormones mediate inflammatory responses
Estrogen, progesterone, and the progesterone metabolite allopregnanolone all play important roles in mediating inflammatory processes.
For example, progesterone stimulates the activation and differentiation of T cells and modulates T cell receptor signaling. It also suppresses cellular cytotoxicity and has been suggested to block degranulation through its effects on progesterone-induced blocking factor.
Progesterone binds to a range of other immune cells, including natural killer cells, macrophages, and dendritic cells. It also binds to non-immune cells, including epithelial and endothelial cells within the airways, where it modulates cellular signaling and activity in ways that mitigate infection.
Estrogens are also potent regulators of immune system processes, exerting anti-inflammatory and neuroprotective effects.
In the innate immune system, estrogen regulates neutrophil chemotaxis and the induction of cytokine-induced chemoattractants and cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. Estrogens also promote the differentiation of dendritic cells and regulate the expression of the chemokine IL-8 and the cytokines IL-6 and IL-10.
Interestingly, in a 2004 preclinical study of SARS-CoV-1 (which caused the 2002 to 2003 SARS outbreak), mild infection caused death in 90% of male mice, compared with only 20% of female mice. More severe infection caused all male mice to die within 5 days, while 50% of the females survived.
Furthermore, gonadectomy increased the death rate among female mice but did not change the death rate among males, thereby supporting a potential protective role of female reproductive steroids against SARS-CoV-1.
How might menopause affect any potential protection?
The decline of estradiol levels during menopause has been shown to reduce the number of B and T cells while increasing the production of proinflammatory cytokines.
“Intriguingly, during menopause, women are at a higher risk for developing diseases,” said Pinna.
Low estradiol levels also increase the expression of the SARS-CoV-2 host cell receptor angiotensin-converting enzyme 2 (ACE2) in the lung, while high levels decrease its expression.
Furthermore, estradiol induces higher levels of antibodies and cells involved in antibody production during the response to viral infection.
Progesterone derivative allopregnanolone also appears to be protective
The progesterone derivative allopregnanolone, which is abundant in the brain, exhibits protective effects in neuropsychiatric disorders, including post-traumatic stress disorder, alcohol use disorder, and Alzheimer’s disease.
These conditions are all characterized by enhanced proinflammatory signaling mediated by the activation of toll-like receptor 4 (TLR4) in the brain and other organs.
One 2019 study of macrophages and monocytes found that allopregnanolone stopped TLR4 binding to its receptor lipopolysaccharide, which increased levels of proinflammatory cytokines and chemokines.
“This effect was also observed in the brain, where TLR4 signal cascade has been demonstrated in neurons and glia,” says Pinna.
Both allopregnanolone and its precursor pregnenolone blocked the entire TLR4 signaling pathway. Both molecules inhibited the binding of TLR4 to myeloid differentiation factor 2 (MD-2) in macrophages and the myeloid differentiation primary response 88 (MYD88) in the brain.
“Since COVID-19 is characterized by excessive TLR4 signals in the lungs… allopregnanolone may protect against COVID-19-induced inflammation,” suggests Pinna.
“Clinical trials should test whether these hormones offer benefits”
Pinna says that overall, the evidence suggests that female reproductive steroids may play a role in COVID-19 sex bias and may account for the more severe symptoms and higher mortality rate observed among men and older individuals.
“These reproductive steroids may be beneficial in preventing or improving COVID-19 symptom severity and mortality,” he writes.
“Clinical trials should test whether these hormones offer benefits in men and in postmenopausal women at risk of developing severe COVID-19 symptoms,” concludes Pinna.
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