Sex Hormones May Be Key Weaponry in the Fight Against COVID-19

Why male patients are at greater risk of severe complications from the Coronavirus

With Franck Mauvais-Jarvis MD, PhD and Patricia Thompson, PhD

Sex differences are routinely observed in comorbidities associated with a poor COVID-19 outcome. Many conditions such as heart disease, hypertension, obesity, and diabetes have distinct sex differences even in the absence of COVID-19. A recent article by Franck Mauvais-Jarvis MD, PhD, Director of the Diabetes Discovery Research and Sex-Based Medicine Laboratory at Tulane University Health Sciences Center and colleagues reviewed the direct role that sex hormones have on immunomodulation in reference to corona virus infections.

It's a pattern that was observed during the SARS-COV and MERS outbreaks, and is present in the current Coronavirus pandemic. Dr. Mauvais-Jarvis says:

“The observation that men have more severe COVID-19 outcomes is likely to be multifactorial, including the fact that women usually mount a stronger immune response to viral infections. This difference in immune response is due to genetic differences in sex chromosomes and possibly the immunomodulation by sex hormones.”

When it comes to corona viruses, men are at greater risk than women

SARS, severe acute respiratory syndrome, is the illness produced by the SARS-COV corona virus which spread across international lines in 2002. Data suggests that sex and age were two independent risk factors for SARS-related mortality. Being male increased the relative risk of death by more than 60%.

MERS, Middle Eastern respiratory syndrome, is also caused by a corona virus and had a substantial outbreak in 2012. A study from Saudi Arabia found that among 425 infected patients, men made up 62% of the cases and had a fatality rate of 52%. Women, on the other hand, had a case fatality rate of only 23%. This pattern was also seen in Korea, where 60% of cases were in men. Most interestingly, this study found that women were more likely to be exposed to the virus because of their higher numbers in the healthcare field, but they still accounted for only 40% of cases. The authors then theorized that women might be less susceptible to MERS infection than men.

COVID-19, our most recent corona virus outbreak, is caused by the SARS-COV2 virus, a close cousin to SARS-COV. Data from the international community, including China, Italy, and the UK, all support the theory that SARS-COV2 infected men are more likely to have severe COVID-19 symptoms and fatal outcomes compared to infected women.

Using data collected at New York City area hospitals between March 1 to April 4, 2020, a new study found that in COVID-19 patients sufficiently sick to require hospitalization, 60% were men. For those admitted to the ICU, 66% were also men. The difference between men and women was also reflected in the COVID-19 mortality rates, and was present at every age point except the youngest subsets.

Why male patients are at greater risk of severe complications from COVID-19

Estrogen and progesterone may be protective against COVID-19

Severe COVID-19 outcomes are associated with a delayed and exaggerated innate immune response. Patients do not necessarily die from viral replication, but from damage produced by the cytokine storm generated by the infection. 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, 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).

In vitro studies using a primate kidney cell line found that selective estrogen receptor modulators (SERMs) inhibited infection with SARS-COV. A mouse study, also using SARS-COV infection rates, found that, as in humans, male mice are significantly more “infected” than female mice, indicated by higher viral titers, more severe lung damage, elevated pro-inflammatory markers, and higher death rates. However, ovariectomized female mice lacking estrogen developed severe lung injury and had a similar death rate as males.

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 to promote the passive transfer of maternal antibodies.

The review by Mauvais-Jarvis et al. points out that pregnancy does not prevent SARS-COV2 infection. At this point, retrospective studies in women have not provided clear indications that pregnancy, and indirectly progesterone, reduce the severity of COVID-19 outcomes.

Dr. Patricia Thompson, Deputy Director for Research at Stony Brook University Cancer Center, which is heading up a current COVID-19 and estrogen clinical trial, told Endocrine Web

“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 COVID19. 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.“   

Androgens could put men at a disadvantage

Recently a pattern has emerged among male COVID-19 patients suggesting that male pattern baldness (androgenetic alopecia) is associated with positive SARS-COV2 infections and a more severe COVID-19 outcome. It's hypothesized that androgens, a key player in this form of baldness, may also be involved in the sex differences observed in COVID-19 patients.

The SARS-COV2 virus gains entry into cells using the ACE2 receptor, facilitated by the serine protease, transmembrane protease, serine 2 (TMPRSS2), an androgen dependent enzyme. TMPRSS2 is up-regulated in prostate cancer. A study by Chakravarty et al. found that men with prostate cancer were more likely to be intubated when infected with SARS-COV2 than men with other cancers. Furthermore, they had a greater likelihood of dying than other male cancer patients. An Italian study confirms that cancer in general is a risk factor for SARS-COV2 infection and that men with prostate cancer are at greater risk than other types of cancer. However, androgen-deprivation therapy seemed to have a protective effect in prostate cancer patients, reducing the likelihood of infection even below that of other cancers.

Can sex hormones be used to combat COVID-19?

There are multiple clinical trials underway seeking to determine if sex hormones can be used to combat COVID-19. Currently active studies include:

NCT 04359329: This study will be comparing a short 7-day course of estradiol (100mg) using a transdermal patch compared to standard care, based on random assignment. They are recruiting patients positive for COVID19 or presumptive positive, both adult men (>= 18yo) and older women (>=55 yo). The primary outcomes are rates of hospitalizations, transfer to ICU, intubations, and mortality. Investigators from Stony Brook University Hospital in New York are heading up this clinical trial.

NCT 04365127: Progesterone treatment is being investigated in this clinical trial sponsored by Cedars-Sinai Medical Center and IBSA Institut Biochimique SA. In this study, twice daily subcutaneous progesterone injections (100mg) will be given for 5 days and compared to standard care procedures in confirmed COVID-19 positive men (>= 18yo) randomly assigned to a treatment group. The primary outcome is the change in status along a 7-point ordinal scale with a range from no hospitalization with no limitations to death. This study is active but not yet recruiting.

NCT 04475601: A collaboration of hospitals in Sweden are conducting a clinical trial to determine if androgen depletion can protect against severe COVID-19 outcomes. Enzalutamide (oral dose 4x40mg) or standard of care will be used to treat male and female COVID-19 patients (>= 50 yo), randomly assigned, for 5 days. The primary outcomes are time to worsen defined by a seven-point ordinal scale, and time to improvement, defined by days to discharge. This study is currently recruiting patients.

Epidemiological data, large healthcare databases, and observant frontline healthcare workers provide valuable insights for researchers on what types of treatments might be beneficial in the fight against COVID-19. Differences between men and women, cancer patients, and even baldness have all revealed possible drug treatment options that are currently being studied in clinical trials.

Dr. Thompson said of the current situation, “Looking forward, it would generally be beneficial to better understand how male and female sex hormone levels influence response to vaccines, anti-viral antibody titers, viral immune response, and clearance. Such knowledge could guide the use of hormones or their targets as immune modulating therapies.” 

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