The Physiological Mechanisms of the Sex-Based Difference in Outcomes of COVID19 Infection

Abstract

The scale of the SARS-CoV-2 pandemic has thrust a spotlight on the sex-based differences in response to viral diseases; morbidity and mortality are greater in men than women. We outline the mechanisms by which being female offers a degree of protection from COVID19, that persists even when confounders such as comorbidities are considered. The physiological and immunological mechanisms are fascinating and range from incomplete X chromosome inactivation of immune genes, a crucial role for angiotensin converting enzyme 2 (ACE2), and regulation of both immune activity and ACE2 by sex steroids. From this flows understanding of why lung and other organs are more susceptible to COVID19 damage in men, and how their distinct immunological landscapes need to be acknowledged to guide prognosis and treatment. Pregnancy, menopause, and hormone replacement therapy bring changed hormonal environments and the need for better stratification in COVID19 studies. We end by noting clinical trials based on increasing estrogens or progesterone or anti-testosterone drugs; excellent examples of translational physiology.

Keywords: ACE2; SARS-CoV-2; hormones; pregnancy; sexual dimorphism; steroid hormones.

FIGURE 1

Sex differences and COVID19. (A) Clinical pathway from confirmed cases, intensive care unit (ICU) admissions and deaths from COVID19. Data from countries providing sex-disaggregated data in October 2020. Redrawn from Global health 5050 at https://globalhealth5050.org/wp-content/uploads/October-2020- The-COVID-19-Sex-Disaggregated-Data-Tracker-Update.pdf, accessed October 16th 2020. (B) Covid19 deaths by country and sex, in March 2020. Chart from Statista at: https://www.statista.com/chart/21345/coronavirus-deaths-by-gender/. (C) deaths from COVID19 grouped by age and sex. Data obtained from 12 countries in May 2020. Redrawn from Global health 5050.

FIGURE 2

SARS-CoV-2 and COVID19. (A) Representation of SARS-CoV-2 virus. (B) A molecular model showing the virus with spike proteins (red) and ACE2 (angiotensin converting enzyme 2) receptor (blue) on host cell surface. From Juan Gaertner/Science Photo Library, accessed 8/11/2020. (C) Covid19 entry via airways. (D) scheme showing TMPRSS activation of virus, followed by its internalization, processing and replication, Adapted from Ward P. et al. (2020). Available at: https://www.fpm.org.uk/blog/covid-19-sars-cov-2-pandemic. Accessed 8/11/2020.

FIGURE 3

Simplified renin-angiotensin system. Scheme shows the role of ACE2 as both the catalysis for Ang(1-7) creation, with a vasodilatory effect on vascular smooth muscle, and as the receptor for SARS-CoV-2. Proteases such as those of the Adam group act to cause shedding of ACE2 into plasma.

FIGURE 4

Serum concentrations of sex steroid hormones. The hormones 17β-estradiol (E2), Progesterone (P4) and Testosterone (T/DHT) in women and men during their life course. In females, E2 and P4 are the predominant hormones. Concentrations increase at puberty, undergo cyclical changes during the menstrual cycle and steadily increase during pregnancy. At menopause, concentrations decline to pre-puberty levels. T/DHT is the predominant male hormone which increases at puberty and remains high until late in life when levels decline steadily.

FIGURE 5

Hormones and COVID19. High E2 and P4 concentrations in females (even higher in pregnancy) helps to suppress proinflammatory cytokine production by macrophages and prevent migration of monocytes and neutrophils into inflamed tissues. CD4 + helper cells are stimulated to produce anti-inflammatory cytokines and T regulatory cells promote immune tolerance. E2 also stimulates production of antibodies. Together, this results in a stronger immune response, faster viral clearance and less severe COVID infection in women. Androgens e.g., T/DHT and AR signaling increases expression of ACE2 and TMPRSS2 promoting viral entry. Together, T/DHT’s immunosuppressive effects, male behavioral factors and co-morbidities can contribute to a more severe COVID infection and worse outcome in males.