key: cord-0789797-lodb579q
authors: Al-Lami, Rasha A.; Urban, Randall J.; Volpi, Elena; Algburi, Ammar M.A.; Baillargeon, Jacques
title: Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19)
date: 2020-05-29
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.013
sha: 8e36436dc41125eee882442b50dd8b333e593d33
doc_id: 789797
cord_uid: lodb579q

Abstract Given the rapid spread of the COVID-19 pandemic and its overwhelming impact on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response—an augmented immune response and cytokine storm—severely damaging the lung tissue and rendering some patients’ conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age associated decreases in sex steroid hormones, namely estrogen and testosterone, may mediate pro-inflammatory increases in older adults that could increase their risk for COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for COVID-19 patients. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy (HRT) in older men and women with COVID-19.

Given the rapid spread of the COVID-19 pandemic and its overwhelming impact on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response-an augmented immune response and cytokine storm-severely damaging the lung tissue and rendering some patients' conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age associated decreases in sex steroid hormones, namely estrogen and testosterone, may mediate pro-inflammatory increases in older adults that could increase their risk for COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for COVID-19 patients. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy (HRT) in older men and women with COVID-19.

ACE2 = Angiotensin-converting enzyme type-2 ACEI = Angiotensin-converting enzyme inhibitor ARB = Angiotensin-II receptor blocker COVID-19 = Corona Virus Infectious Disease HRT = hormone replacement therapy IL-1/6 = Interleukin-1/6 MERS = Middle East Respiratory Syndrome NF-κB = Nuclear factor kabba-B SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2 TNF-α = Tumor necrosis factor-alpha Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rapidly spread worldwide. To date, no specific therapeutic agents or vaccines for coronavirus disease 2019 are available, and much information on the causative agent, SARS-CoV-2, is lacking. However, descriptive reports have consistently shown that older adults and males are at increased risk of mortality from COVID-19 and that the protective effect of younger age occurs in both males and females. 1-3 As we search for treatment strategies for COVID-19, understanding the extent to which sex hormones underlie these differential case-fatality rates holds broad clinical and public health relevance.

For the majority of infectious diseases, females have been consistently observed to mount a stronger immune response than males. 4 In general, the female immune system responds more efficiently to pathogens, producing higher amounts of interferons and antibodies; however, this protective effect-mediated primarily by estrogen-is attenuated in post-menopausal women. 5 Briefly, SARS-CoV-2 enters the cell via the angiotensin converting enzyme-2 receptor (ACE2R) which is expressed by pneumocytes and leads to the downregulation of ACE 2 levels. ACE 2 is normally responsible for converting angiotensin-II (Ang II) into vasodilatory and less immune augmenting variants of angiotensin. Ang II binds type 1 angiotensin receptors (AT1R) in the lung to induce vasoconstriction and inflammation via activation of the NF-κB pathway, which increases cytokines synthesis. 9 Low levels of ACE 2 and high levels of Ang II lead to increased pulmonary vessel permeability which subsequently results in inflammatory damage to the lung tissue. 10 The proposed primary culprit of severe COVID-19 is the cytokine storm resulting from an unchecked inflammatory response that damages the lung tissue rendering some patients' condition severe enough to require assisted ventilation and-in a substantial percentage of cases-causes death. 11 A study of influenza patients showed that high cytokine levels and low T-lymphocyte levels was predictive of high pharyngeal viral loads and increased mortality. 12 These findings are consistent with COVID-19 lab findings which support the hypothesis that the augmented immune response resulting in the circulation of tissue damaging cytokines is the primary mediator in pulmonary viral infection. 11 It is also possible that SARS-CoV-2 directly activates mast cells, which are found in respiratory tract submucosa, with the subsequent release of pro-inflammatory cytokines like IL-1. 13 Sex differences in inflammation have been well documented and attributed to various factors. Although most of the immune regulatory genes are encoded by X chromosomes-resulting in women's generally stronger immune response-this sex difference in inflammatory response is postulated to be largely driven by sex hormones. 14 While estrogen has a complex role in modulating the immune systemgenerally in a dose-dependent manner-it is reported to have an anti-inflammatory effect at normal physiologic levels in premenopausal women. 5, 15 Most cytokinesnamely Il-6, IL-8 and TNF-α-are inhibited by periovulatory dosages of estrogen while low levels of estradiol can augment inflammatory mediators which could explain the proinflammatory states that most postmenopausal women suffer from (e.g. atherosclerosis). 5 Post-menopausal women are reported to have higher levels of proinflammatory cytokines, such as IL-1, IL-6, IL-and TNF-α; however, these levels are reduced with the use of hormone replacement therapy (HRT) -especially estrogen containing types-to pre-menopausal levels. 14 Moreover, estrogen-containing contraceptive methods have been shown to enhance cellular immunity in HIV-infected patients. 16 Female mice receiving high levels of estrogen are reported to have increased survival and lower cytokine production in the lung following influenza infection. 4 Likewise, the activated estrogen receptor, specifically ERα, has been shown to inhibit NF-κB mediated inflammation response and cytokine production via immune cells, lymphocytes, macrophages and neutrophils. 17 The finding that Ang II activates the NF-κB pathway to increase cytokine synthesis after SARS infection while estrogen can shut down the NF-κB pathway holds possible relevance for COVID-19 treatment strategies in female patients.

Estrogen's anti-inflammatory effect against coronaviruses is supported by several animal studies. 18 First, researchers who infected male and female mice with SARS-CoV reported that male mice had a worse prognosis than female mice. Specifically, after SARS-CoV infection, male mice had higher viral titers, more pulmonary vascular permeability and/or alveolar edema and more inflammatory monocytes and macrophages in their lungs compared to age-matched female mice. 18 Second, SARS-CoV infected female mice that were estrogen-depleted by oophorectomy or estrogen receptor blocker had a worse SARS-CoV prognosis. 18 Although COVID-19 patients suffer from lymphopenia, which might cast doubt on the estrogen anti-inflammatory effect, these findings were independent of T or B lymphocyte action. 18 In view of the close genomic similarity of SARS-CoV-2 and SARS-CoV, 19 it is possible that estrogen plays a similarly protective role against SARS-CoV-2.

Although females have accounted for a lower number of COVID-19 cases than males, 20 it is important to assess why-among men infected with SARS-CoV-2younger age is strongly protective against adverse outcomes. It is possible that testosterone has a protective anti-inflammatory effect in younger men, analogous to the effect of estrogen in younger women. Testosterone is reported to have antiinflammatory functions via suppression of both the cellular and humoral immune systems. In fact, testosterone was shown to lower IL-6 and TNF-α via inhibition of the NF-κB pro-inflammatory pathway, analogous to estrogen. 21 Moreover, testosterone deficiency has been linked with autoimmune disease and increases in inflammatory markers, such as C-reactive protein (CRP). 22, 23 In a laboratory study, removal of gonads from influenza virus infected male mice resulted in higher death rates compared to gonadally intact male mice. 4 Low levels of testosterone, as can occur in normally aging men, have also been linked with high inflammatory markers like IL-6 and may underlie their increased risk of lung damage after pneumonia. 24, 25 Importantly, testosterone can be peripherally converted to estrogen via aromatase enzyme which might add an anti-inflammatory impact. 26 It is also plausible that testosterone might reduce the need for assisted ventilation through its anti-catabolic role on respiratory muscles. 27 A recent study showed that hypogonadism was common in mechanically-ventilated patients with acute respiratory failure and was strongly associated with longer ICU stays. 28 Several smallscale clinical studies indicate that testosterone therapy may improve outcomes in hospitalized COPD patients. 29 Further research is needed on this potential effect.

Although genetic factors can explain some of the sex differences in COVID-19 patients-women, as a result of their extra X chromosome, have stronger immune function and more efficient viral clearing-these factors might not explain the dramatic within-gender case-fatality differentials observed across age groups. 2, 30 A recent study showed that comorbidities among COVID-19 patients include hypertension, diabetes and obesity 2 -all of which are associated with inflammation that could have put older patients at higher risk to COVID-19 death for which estrogen and testosterone hold potential therapeutic modalities.

In evaluating sex and age case-fatality rate disparities of all three recent coronavirus epidemics, it is also important to consider the following potential confounders. First, males' higher mortality rate may be driven, in part, by their higher rates of smoking, which increases vulnerability of lung tissues to viral infection and other lifestyle factors, which increase their rates of underlying cardiovascular disease and diabetes. 31 Second, it is important to acknowledge that the increased mortality in older adults with COVID-19, both males and females, may be partly attributable to concurrent morbidities, especially cardiovascular diseases and diabetes. In addition, there is concern that these associations are driven by specific antihypertensive medications, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) drugs, both of which increase the expression of ACE 2 receptors (ACE2R) if taken chronically, which could increase the risk for COVID-19 adverse outcomes. 32 Nevertheless, Gurwitz suggested that patients chronically treated with angiotensin receptor (AT1R) blocker (e.g. Losartan) should have had better prognosis after being infected with SARS-CoV-2 virus. 10 This viewpoint is supported by the finding that once SARS-CoV-2 infects the lung, ACE 2 is downregulated, increasing the availability of pro-inflammatory angiotensin-II, which leads to lung damage by binding the AT1R.

Thus, AT1R blockers (i.e. reducing angiotensin-II effects) could protect the patient from excess inflammation and lung damage due to cytokine storm. Furthermore, a recent study of 5700 COVID-19 patients treated in New York reported that the mortality rate was modestly higher for patients receiving ACEIs (32.7%) and/or ARBs (30.6%) compared with those not taking these medications (26.7%). 2 Exogenous estrogen and testosterone therapy have therapeutic potential to mitigate the damaging inflammatory response to SARS-CoV-2 without hampering the immune system's response to the virus, as corticosteroids do 33 Recently, investigators have suggested the use of immune modulating drugs to block inflammatory markers' receptors in order to mitigate the amplified and tissue damaging immune response of SARS-CoV-2 (e.g. Anarka [an IL-1 receptor blocker], Tocilizumab and Sarilumab [IL-6

receptor antagonists]. 8, 33, 34 However, there are concerns about these agents' possible adverse effects on patients' immune function.

In view of the well documented role of sex hormones in immune responsespecifically the anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone-it is important to consider their potential role in developing treatment strategies for COVID-19 patients, particularly older adults and those with hormone deficiencies. Assessing the disease progression and outcomes of such patients, with particular attention to underlying mechanisms, may provide important clinical insight. Future research is needed to examine whether hormone replacement therapy (HRT) may have a pharmacotherapeutic role in treating older adults diagnosed with COVID-19.

Authors declare acknowledgements to Melinda Sheffield-Moore, PhD, College of Education and Human Development, Texas A&M University for her professional opinion.

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