article · Biomedicine & Pharmacotherapy
Severe COVID-19 displays notable sex disparities, with males experiencing higher incidence rates and fatalities than females. A major driver of this difference appears to be the female immune system, which is more responsive, robust, and capable of modulating cytokine storms. In contrast, severe inflammation in males frequently accelerates progression from mild to severe illness. Functional levels of sex hormones underpin these distinct immune reactions. Estrogen protects females by dampening severe inflammation, whereas androgen is implicated in over-activating immune cells, facilitating cytokine storms, and triggering extensive tissue damage. Biological mechanisms involving the immune system, sex hormones, and the angiotensin-converting enzyme system explain this male predisposition. Based on these mechanisms, several prospective therapeutic strategies warrant consideration for tackling COVID-19, including estrogen-based therapies, androgen deprivation therapies, and angiotensin-converting enzyme inhibitors.
Understanding sex-based differences in COVID-19 severity clarifies why males suffer worse outcomes and higher death rates. By highlighting how sex hormones influence immune responses and inflammation, this work helps guide clinicians and researchers towards targeted medical interventions. Identifying biological drivers such as androgens and estrogen enables more tailored, sex-specific strategies to manage severe disease and reduce mortality.
This review highlights therapeutic concepts, specifically androgen deprivation therapy, estrogen-based treatments, and angiotensin-converting enzyme inhibitors, for pharmaceutical developers and clinical trial sponsors. The insights reflect early-stage exploratory research rather than direct clinical testing. Any prospective commercial application or drug repurposing strategy remains at an early investigational distance from real-world use, requiring rigorous validation in clinical studies.
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The severe form of COVID-19 has significant sex disparities, with high fatalities commonly reported among males than females. The incidence of COVID-19 has also been higher in males compared with their female counterparts. This trend could be attributed to a better responsive and robust immune system in females. Cytokine storm is one of the pathophysiological features of severe COVID-19, and it occurs as a result of over-activation of immune cells leading to severe inflammation and tissue damage. Nevertheless, it is well modulated in females compared to their male counterparts. Severe inflammation in males is reported to facilitate progression of mild to severe COVID-19. The sex hormones, estrogens and androgens which exist in varying functional levels respectively in females and males are cited as the underlying cause for the differential immune response to COVID-19. Evidence abounds that estrogen modulate the immune system to protect females from severe inflammation and for that matter severe COVID-19. On the contrary, androgen has been implicated in over-activation of immune cells, cytokine storm and the attendant severe inflammation, which perhaps predispose males to severe COVID-19. In this review efforts are made to expand understanding and explain the possible roles of the immune system, the sex hormones and the angiotensin-converting enzyme (ACE) systems in male bias to severe COVID-19. Also, this review explores possible therapeutic avenues including androgen deprivation therapy (ADT), estrogen-based therapy, and ACE inhibitors for consideration in the fight against COVID-19.
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DOI: 10.1016/j.biopha.2020.110748
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