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In an article recently published on Trends in endocrinology and metabolism, Graziano Pinna of the University of Illinois at Chicago outlines some of the evidence that suggests that female reproductive hormones may play a role in the sexual bias that has been observed in coronavirus disease 2019 (COVID-19).
Reports have shown that severe symptoms of COVID-19 and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occur more frequently in men than in women, suggesting that female reproductive hormones may play a role. protective role.
Now, Pinna has described some of the effects estrogen and progesterone have on the immune system that can help prevent severe symptoms and death from COVID-19.
Pinna provides examples of how hormones exert anti-inflammatory actions, remodel the competence of immune cells and stimulate higher levels of antibodies against viruses.
It is now asking for clinical trials to investigate whether these hormones could be useful for postmenopausal men and women who are at risk of developing severe COVID-19.
Hormones mediate inflammatory responses
Estrogen, progesterone and the progesterone metabolite allopregnanolone all play an important role in mediating inflammatory processes.
For example, progesterone stimulates T cell activation and differentiation 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 number 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 cell signaling and activity in ways that mitigate infection.
Estrogens are also powerful regulators of immune system processes, exerting anti-inflammatory and neuroprotective effects.
In the innate immune system, estrogens regulate neutrophil chemotaxis and the induction of chemotactic and cytokine-induced cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL- 1β. Estrogens also promote dendritic cell differentiation and regulate the expression of the chemokine IL-8 and cytokines IL-6 and IL-10.
Interestingly, in a 2004 preclinical study of SARS-CoV-1 (which caused the SARS outbreak from 2002 to 2003), a mild infection caused death in 90% of male mice, compared to only 20 % of females. A more severe infection caused all male mice to die within 5 days, while 50% of females survived.
Furthermore, gonadectomy increased the mortality rate among female mice but did not change the mortality rate among males, thus supporting a potential protective role of female reproductive steroids against SARS-CoV-1.
How could menopause affect any potential protection?
Decreasing estradiol levels during menopause have been shown to reduce the number of B and T cells by increasing the production of proinflammatory cytokines.
“Curiously, during menopause, women are at an increased risk of developing diseases,” Pinna said.
Low levels of estradiol also increase the expression of the host cell SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) in the lung, while high levels reduce its expression.
Additionally, estradiol induces higher levels of antibodies and cells involved in antibody production during the response to viral infection.
Allopregnanolone, a progesterone derivative, 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 an increase in proinflammatory signaling mediated by activation of the toll-like receptor 4 (TLR4) in the brain and other organs.
A 2019 study in macrophages and monocytes found that allopregnanolone disrupted the binding of TLR4 to its lipopolysaccharide receptor, which increased levels of proinflammatory cytokines and chemokines.
“This effect has also been seen in the brain, where the 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 primary myeloid differentiation response 88 (MYD88) in the brain.
“Because COVID-19 is characterized by excessive TLR4 signals in the lungs … allopregnanolone can protect against COVID-19-induced inflammation,” suggests Pinna.
“Clinical trials should investigate whether these hormones offer benefits”
Pinna says that overall, the evidence suggests that female reproductive steroids may play a role in COVID-19 sexual injury and may explain the more severe symptoms and higher death rate observed among men and older individuals.
“These reproductive steroids may be useful in preventing or improving the severity and mortality of COVID-19 symptoms,” he writes.
“Clinical trials should investigate whether these hormones offer benefits in postmenopausal men and women at risk of developing severe symptoms of COVID-19,” concludes Pinna.
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