Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes

Abstract

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.

Keywords: COVID-19; cytokine storm; estrogen; immunomodulation; progesterone; sex difference.

Figure 1.

Anti-inflammatory and immunomodulatory actions of estradiol and progesterone. High physiological concentrations of 17β-estradiol (E2) suppress the production of proinflammatory cytokines, for example, interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α), and chemokine CCL2 by macrophages, thus preventing neutrophils and monocytes migration into inflamed areas. Progesterone (P4) also inhibits proinflammatory cytokines IL-1β and interleukin 12 production by macrophages and dendritic cells. High concentrations of E2 or P4 stimulate CD4+ T-helper cell production of anti-inflammatory cytokines, for example, interleukin 4 and interleukin 10, and favor Th2-type anti-inflammatory responses. E2 and P4 also enhance the expansion of regulatory T cells (Treg), thus promoting immune tolerance. Finally, E2 stimulates antibody production by B cells.