Good news for those of you who are currently on hormone replacement therapy especially if you’re a woman — new research suggests that sex steroids may play a role in keeping people from developing severe COVID-19 symptoms. One trend that has emerged is the tendency for males to have a more difficult experience with the disease than females. The ratio of COVID-19 deaths are higher among men than women. For every 100 women who die, 135 men die from the disease.
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 play a role in the sex bias that has been observed in coronavirus disease COVID-19.
Graziano Pinna, a research associate professor of psychiatry, analyzes existing research in his “Sex and COVID-19: A protective role for reproductive steroids” to look at why COVID-19 symptom severity and mortality are more frequent in men and older people than in women. His paper suggests that female reproductive steroids play a protective role. Pinna observes that, “Pregnant women are 15 times less likely to die from COVID than other women. This observation in pregnant women provides significant scientific background, not only as to why women are more protected than men, but also why older people are less protected than younger people, because we know the older you are, the more decreased your hormones are.”
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 may block degranulation through its effects on progesterone-induced blocking factor. Both estradiol and progesterone have anti-inflammatory properties and can reshape competence of immune cells and stimulate antibody production. Allopregnanolone, a metabolite of progesterone, rapidly modulates GABAA receptors in neurons, which is associated with mood and cognition improvement. It also affects immune-competent cells and induces potent anti-inflammatory functions.
Severe COVID-19 outcomes are associated with a delayed and exaggerated innate immune response. Patients do not necessarily die from viral replication, but rather from damage produced by the cytokine storm generated by the infection. A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. In an attempt to protect the body, immune cells infiltrate organ tissues with a hyper-activation of monocytes, and macrophages produce large quantities of primary pro-inflammatory cytokine, IL6, along with IL1beta and TNF-alpha. In the review article by Jarvis et al., the authors propose that estrogen and estrogen receptors are key in limiting cytokine storm, that estrogen receptors are present on all immune cells, and that treatment with estrogen, as indicated in both human and animal studies, reduces the innate immune response, lowers pro-inflammatory cytokines (IL6, IL1beta, TNF-alpha), and elevates anti-inflammatory cytokines (IL4, IL10, Interferon-gamma). Progesterone is another immunomodulating sex hormone that could be utilized in the battle against COVID-19. In the presence of progesterone, CD4+ T-helper cells skew from Th-1 to Th-2 in the production of anti-inflammatory cytokines, specifically IL4 and IL10. This is all part of the shift in the innate and adaptive immune responses observed during pregnancy, including reducing pro-inflammatory responses to avoid fetal rejection, and promoting the passive transfer of maternal antibodies.
Dr. Patricia Thompson, Deputy Director for Research at Stony Brook University Cancer Center, which is heading up a COVID-19 and estrogen clinical trial, comments, “Both estrogen and progesterone have shown immune modulating activity through their individual receptors on cells. At this time, we do not know if estrogen or progesterone would be better at modulating patient immune response to COVID-19. Our interest in estrogen stems from prior evidence of the effects of estrogen through expression of its receptor on immune cells to enhance antibody responses and viral clearing immune responses.
In contrast, progesterone has been shown to have greater immunosuppressive effects. This may be more important in preventing later inflammatory effects. These sex specific hormone differences and immune responses have been observed for some time, though relatively understudied. The pandemic and differences in COVID-19 morbidity and mortality by age and sex have raised attention to these questions, and to the therapeutic potential of sex hormones as short-acting immune modulatory drugs in fighting infectious diseases.”
There are currently many clinical trials underway that seek to determine whether sex hormones can be used to combat COVID-19. The studies mentioned above are very promising, and they provide another reason why sex hormones are important in our overall functioning. With the loss of hormones, whether due to aging or procedural loss such as a hysterectomy, our bodies are not as equipped to run at optimum, and we are more vulnerable to disease. If you are concerned about your own hormonal balance and would like to know your baseline levels, we provide comprehensive testing at TLC Medical Centre Pharmacy. As a Board Certified anti-aging, regenerative, and functional medicine practitioner, I can help you get your body back in balance to improve not only your immunity but even your overall health.
