Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D

Abstract

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.

Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection

“…In the human population, there have been reports of an increase in COVID-19 severity in males (31,32) as well as a disparity of COVID-19 severity among different age groups (33,34). In these studies, neither age nor gender was a factor in disease severity or outcome.…”

Age and gender distribution of COVID-19 infected cases in Italian population

“…It is known that adequate vitamin D levels would contribute to reduce in ammation and acute respiratory tract infection. Many authors speculate that, among other factors, the different susceptibility to virus infection may be the consequence of lower vitamin D levels in men in their sixties, compared with age-matched women [26].…”

The Neurological Aspects of COVID-19: Do Women Respond Differently?

“…Men are more predisposed to complications. Sex hormones may modulate the expression of ACE-2, as suggested by La Vignera et al 28 Role for androgen receptor gene polymorphisms need to be excluded in the pathogenesis of SARS-CoV-2. 29 The immunological aspect of sex hormones has also been under scrutiny in COVID-19 times.…”