Dr. Ron’s Research Review – June 24, 2020

©

This week’s research review focuses on Coronavirus and Estrogen and Testosterone

 

17β-Estradiol, a Potential Ally to Alleviate SARS-CoV-2 Infection

A study discussed the sex differences and the role of estradiol in modulating the lung and systemic inflammatory response, focusing on its possible application as a treatment modality for SARS-CoV-2 patients. (Breithaupt-Faloppa et al., 2020)
COVID-19 patients develop severe hypoxemia early in the course of the disease, which is silent most of the time. Small fibrinous thrombi in pulmonary arterioles and a tumefaction of endothelial were observed in the autopsies of fatal COVID-19 cases. Studies showed that the viral infection induces a vascular process in the lung, which included vasodilation and endothelial dysfunction. Further, the proportions of CD4+ T and CD8+ T lymphocytes were strongly reduced in patients with severe SARS-CoV-2 infection.
Estradiol is connected with CD4+ T cell numbers and increases T-reg cell populations, affecting immune responses to infection. It is known that estradiol exerts a protective effect on endothelial function, activating the generation of nitric oxide (NO) via endothelial nitric oxide synthase.
Estrogen attenuates the vasoconstrictor response to various stimuli and induces vasodilation in the pulmonary vasculature during stress situations like hypoxia. It exerts a variety of rapid actions, which are initiated after its coupling with membrane receptors, which in turn, may positively modulate vascular responses in pulmonary disease and help to maintain microvascular flow.
Direct and indirect mechanisms underlying the effects of estradiol were investigated, and the results point to a possible protective effect of estradiol against COVID-19, indicating that it may be considered as an adjuvant therapeutic element for the treatment of patients affected by the novel coronavirus.

Estrogens and the Gendered Impact of COVID-19

Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women, there seem to be sex differences in mortality rate and vulnerability to the disease. More men than women are dying from COVID-19. (Grandi et al., 2020)
A study explored the potential role of estrogens in this COVID-19 gendered impact.
Estrogens stimulate the humoral response to viral infections, while testosterone and progesterone give an immune suppression of both innate and cell-mediated immune responses.
Estrogens, in particular estradiol but also synthetic estrogen such as ethinylestradiol, could protect women from the most serious complications of COVID-19.
The use of medications that keep hormonal levels high and stable, such as combined hormonal contraceptive, could therefore play a protective role. These potential benefits overtake the thrombotic risk in healthy women. As stated by the World Health Organization, all modern methods of contraception were safe to use during the COVID-19 pandemic.

Sex-Specific SARS-CoV-2 Mortality: ACE2 and Hypovitaminosis D

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease (COVID-19) appears to have a higher mortality rate in presence of comorbidities and in men. (La Vignera et al., 2020)
The latter suggests the presence of a possible sex-dependent susceptibility. An enzymatic system involved in this different predisposition could be represented by angiotensin converting enzyme 2 (ACE2). ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells and myocardium.
Data on the experimental animal have shown that 17ß-estradiol increases the expression and activity of ACE2 in both adipose tissue and kidney. Spontaneously hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decrease after orchiectomy.
In addition to this first aspect, the recent evidence of an increased frequency of venous thromboembolism in patients with COVID-19 (a clinical element associated with a worse prognosis) calls the attention on the safety of treatment with testosterone, in particular in hypogonadal men with greater genetic predisposition.
Evidence that sex hormones are able to modulate the expression of ACE2 could help in interpreting epidemiological results and in designing more appropriate intervention strategies.
Moreover, the vitamin D deficiency in elderly men may be worthy of further study regarding the epidemiological aspects of this different susceptibility and lethality between sexes.

Low Testosterone Predicts Adverse Outcomes in SARS-CoV-2 Pneumonia

A study estimated the association between T level and SARS-CoV-2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU).  (Rastrelli et al., 2020)
A consecutive series of 31 male patients affected by SARS-CoV-2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the "Carlo Poma" Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D-dimer, fibrinogen, interleukin 6 (IL-6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were determined.
Lower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L.
This study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS-CoV-2-infected men admitted to RICU.

Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells. (Stelzig et al., 2020)  Download

Exogenous Estrogen Treatment for both Men and Women

In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19.
We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources.
Premarin can exert similar ER up-regulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic. (Suba, 2020)

 

Dr. Ron

 


Articles

 

17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection.
            (Breithaupt-Faloppa et al., 2020)  Download
Considering that female sexual hormones may modulate the inflammatory response and also exhibit direct effects on the cells of the immune system, herein, we intend to discuss the sex differences and the role of estradiol in modulating the lung and systemic inflammatory response, focusing on its possible application as a treatment modality for SARS-CoV-2 patients. COVID-19 patients develop severe hypoxemia early in the course of the disease, which is silent most of the time. Small fibrinous thrombi in pulmonary arterioles and a tumefaction of endothelial were observed in the autopsies of fatal COVID-19 cases. Studies showed that the viral infection induces a vascular process in the lung, which included vasodilation and endothelial dysfunction. Further, the proportions of CD4+ T and CD8+ T lymphocytes were strongly reduced in patients with severe SARS-CoV-2 infection. Estradiol is connected with CD4+ T cell numbers and increases T-reg cell populations, affecting immune responses to infection. It is known that estradiol exerts a protective effect on endothelial function, activating the generation of nitric oxide (NO) via endothelial nitric oxide synthase. Estrogen attenuates the vasoconstrictor response to various stimuli and induces vasodilation in the pulmonary vasculature during stress situations like hypoxia. It exerts a variety of rapid actions, which are initiated after its coupling with membrane receptors, which in turn, may positively modulate vascular responses in pulmonary disease and help to maintain microvascular flow. Direct and indirect mechanisms underlying the effects of estradiol were investigated, and the results point to a possible protective effect of estradiol against COVID-19, indicating that it may be considered as an adjuvant therapeutic element for the treatment of patients affected by the novel coronavirus.

The gendered impact of coronavirus disease (COVID-19): do estrogens play a role
            (Grandi et al., 2020) Download
<b>Objective:</b> Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women, there seem to be sex differences in mortality rate and vulnerability to the disease: more men than women are dying. <b>Methods:</b> We have explored the potential role of estrogens in this COVID-19 gendered impact. <b>Results:</b> Estrogens stimulate the humoral response to viral infections, while testosterone and progesterone give an immune suppression of both innate and cell-mediated immune responses. We hypothesise that estrogens, in particular estradiol but also synthetic estrogen such as ethinylestradiol, could protect women from the most serious complications of COVID-19. The use of medications that keep hormonal levels high and stable, such as combined hormonal contraceptive, could therefore play a protective role. These potential benefits overtake the thrombotic risk in healthy women. As stated by the World Health Organization, all modern methods of contraception were safe to use during the COVID-19 pandemic.

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D.
            (La Vignera et al., 2020) Download
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease (COVID-19) appears to have a higher mortality rate in presence of comorbidities and in men. The latter suggests the presence of a possible sex-dependent susceptibility. An enzymatic system involved in this different predisposition could be represented by angiotensin converting enzyme 2 (ACE2). ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells and myocardium. Data on the experimental animal have shown that 17ß-estradiol increases the expression and activity of ACE2 in both adipose tissue and kidney. Spontaneously hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decrease after orchiectomy. In addition to this first aspect, the recent evidence of an increased frequency of venous thromboembolism in patients with COVID-19 (a clinical element associated with a worse prognosis) calls the attention on the safety of treatment with testosterone, in particular in hypogonadal men with greater genetic predisposition. Evidence that sex hormones are able to modulate the expression of ACE2 could help in interpreting epidemiological results and in designing more appropriate intervention strategies. Moreover, the vitamin D deficiency in elderly men may be worthy of further study regarding the epidemiological aspects of this different susceptibility and lethality between sexes.

Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients.
            (Rastrelli et al., 2020) Download
BACKGROUND:  The pandemic of new severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS-CoV-2) has stressed the importance of effective diagnostic and prognostic biomarkers of clinical worsening and mortality. Epidemiological data showing a differential impact of SARS-CoV-2 infection on women and men have suggested a potential role for testosterone (T) in determining gender disparity in the SARS-CoV-2 clinical outcomes. OBJECTIVES:  To estimate the association between T level and SARS-CoV-2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU). MATERIALS AND METHODS:  A consecutive series of 31 male patients affected by SARS-CoV-2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the "Carlo Poma" Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D-dimer, fibrinogen, interleukin 6 (IL-6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were determined. RESULTS:  Lower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L. DISCUSSION AND CONCLUSION:  Our study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS-CoV-2-infected men admitted to RICU.

Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells.
            (Stelzig et al., 2020)  Download
There is marked sexual dimorphism in the current COVID-19 pandemic. Here we report that estrogen can regulate the expression of ACE2, a key component for SARS-CoV-2 cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.

Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients.
            (Suba, 2020)  Download
The presented work summarizes the results of studies underlining the crucial role of estrogen receptor (ER) signaling in both innate and adaptive immune responses as well as in tissue repairing processes during respiratory virus infection. Experimental studies justify that among respiratory virus infected mice, a weaker ER signaling leads to increased morbidity and mortality in both males and females. In animal experiments, estrogen treatment silences the inflammatory reactions and decreases virus titers leading to improved survival rate; it seems to be an ideal prevention and therapy against COVID-19. We should overcome the widespread reluctance to estrogen therapy as we have a unique estrogen formula; conjugated estrogens, or conjugated equine estrogens available under the brand name of Premarin deriving from natural sources. Premarin can exert similar ER upregulative and gene repairing power like endogenous estrogen without any risk for adverse reactions. Premarin is capable of stopping the COVID-19 pandemic.

 


References

Breithaupt-Faloppa, AC, et al. (2020), ‘17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection.’, Clinics (Sao Paulo), 75 e1980. PubMed: 32490931
Grandi, G, F Facchinetti, and J Bitzer (2020), ‘The gendered impact of coronavirus disease (COVID-19): do estrogens play a role’, Eur J Contracept Reprod Health Care, 1-2. PubMed: 32469251
La Vignera, S, et al. (2020), ‘Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D.’, Int J Mol Sci, 21 (8), PubMed: 32331343
Rastrelli, G, et al. (2020), ‘Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients.’, Andrology, PubMed: 32436355
Stelzig, KE, et al. (2020), ‘Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells.’, Am J Physiol Lung Cell Mol Physiol, PubMed: 32432918
Suba, Z (2020), ‘Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients.’, J Pharm Pharm Sci, 23 (1), 75-85. PubMed: 32324533