Sexual dimorphism in COVID-19: potential clinical and public health implications

Abstract

Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.

Figure 1

Systemic and molecular basis for sexual dimorphism in COVID-19 SARS-CoV-2 uses its spike glycoprotein (S) to attach to the host cell, triggering fusion between virus and lipid membrane (exocytosis). ACE2, TMPRSS2, and DPP4 are critical mediators of this process and show tissue-specific and sex-specific expression patterns. Higher expression of TMPRSS2 and DDP4 in men is associated with increased viral binding and entry, leading to higher viral load compared with women. Oestrogens and androgens regulate the subsequent immune response. Women exhibit a stronger immune response, which is characterised by, among other factors, the release of anti-inflammatory cytokines (eg, IL-6, IL-1β, TNFα). In men, on the other hand, pro-inflammatory cytokines (eg, IL-4, IL-10) dominate. Sex-related differences in the response to stress further contribute to the predisposition of men to a pro-inflammatory state. An overall increased basal activity of the hypothalamic–pituitary–adrenal axis in women, mediated by oestrogens, results in increased cortisol concentrations compared with men. Decreased concentrations of anti-inflammatory cortisol further contribute to the pro-inflammatory status in men, possibly causing more severe COVID-19 courses in men compared with women. Other factors, such as age, smoking, alcohol consumption, and presence of comorbidities further contribute to the increased risk of severe disease and higher case fatality rates in men. Plus symbols mark an activation and minus symbols mark an inhibition. ACE2=angiotensin-converting enzyme 2. ACTH=adrenocorticotropic hormone. ADH=antidiuretic hormone. CRH=corticotropin-releasing hormone. DPP4=dipeptidyl peptidase-4. TMPRSS2=transmembrane protease serine subtype 2.

Figure 2

Sexual dimorphism in severity and mortality of COVID-19 Men experience more severe disease courses and more deaths connected to COVID-19, but women appear to be at increased risk of long COVID. Therefore, we argue that sex should be taken in consideration regarding COVID-19 treatment, follow-up, and establishment of public health measures.