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Summary

The article by Mauvais-Jarvis et al. [1] is a mini-review that highlights experimental evidence on the potent immunomodulatory role of steroid hormones 17β-estradiol (E2) and progesterone (P4). The review discusses how different concentrations of estrogens, P4, and androgens between women and men and genetic factors may explain the lower mortality in women compared to men. Moreover, the role of the proinflammatory cytokine storm in coronavirus disease, how females exhibit more significant immune responses to viruses, the evolution f coronavirus disease in èregnant women and the immune-modulatory function of estrogen-progestin therapies are illustrated. The authors also claim that acute combined E2 and P4 treatment may represent a safe and viable strategy that deserves to be tested in clinical trials to mitigate severe COVID-19 outcomes. The possibility of off-label use of these approved drugs for human use as potentially life-saving therapeutics needs to be explored.

Commentary

In China, Europe, and the United States, Covid-19 severity and mortality are consistently lower in women than men [1]. The rate of confirmed SARS-CoV-2 infections is age-dependent and greater in males younger than ten and older than 50 years [2]. In the attempt to understand this apparent female-biased protection, it became evident that patients with COVID-19 do not die from damage caused by virus replication but rather from the consequences of a so-called “cytokine storm.” The Wuhan report [3] first pointed to immune cells that infiltrate the lungs and cause elevated proinflammatory cytokines (e.g. interleukin-6), tumour necrosis factor and chemokines and also lymphopenia. A local outpouring of chemokines and cytokines attracts more inflammatory cells such as neutrophils and monocytes into lung tissue with resultant lung injury. The host, rather than being protected, will experience respiratory distress and multiorgan failure.

How can steroid hormones E2 and P4 therapy mitigate the virus-induced innate immune inflammatory response and thereby mimick relative female COVID-19 protection? E2 receptors are expressed in all and P4 receptors in most immune cells and may serve as transcriptional regulators of cellular function [4]. Experimentally, E2 suppresses the production of proinflammatory cytokines by monocytes and macrophages, thereby preventing migration into inflamed areas [5]. Generally, E2 favours T-cell type 2 anti-inflammatory responses, enhancing the expansion of regulatory T-cells, thus promoting immune tolerance and stimulating antibody production by B-cells [6].

In patients with confirmed COVID-19, acute therapy with E2 and P4 could mitigate the cytokine storm while increasing antibody production; it is expected to blunt innate immune inflammatory responses and, at the same time, stimulate B-cell responses without noticeable side effects. The advantage of available sex hormone compounds is the depth of knowledge regarding their clinical efficacy and toxicity accumulated from decades of clinical and basic studies [1].

On a personal note, I self-administered 25ug Estradiol-hemihydrate patch, because of a slow recovery from COVID disease, with quick improvement in respiratory volume, heart rate, exercise tolerance and quality of sleep.

Currently, two clinical trials are testing E2 (ClinicalTrials.gov identifier NCT04359329 or P4 (ClinicalTrials.gov identifier NCT04365127) individually in COVID-19 patients [1] while waiting for a safe and efficient vaccine to be developed.

Hermann P. G. Schneider
Emeritus Professor of Obstetrics & Gynecology, Retired Chief of the Department of Obstetrics & Gynecology, University of Muenster Medical School, Muenster, Germany

References

  1. Mauvais-Jarvis F, Klein SL, Levin, ER. Estradiol, Progesterone, Immunomodulation, and-COVID-19 Outcomes. Endocrinology 161: 1-8, 2020.
    https://pubmed.ncbi.nlm.nih.gov/32730568/
  2. Marina S, Piemonti L. Gender and age effects on the rate of infections and deaths in individuals with confirmed SARS-CoV-2 infection in six European countries. SSRN website.
    https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3576790
  3. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect 80(6):607-613, 2020.
    https://pubmed.ncbi.nlm.nih.gov/32283152/
  4. Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 97(1): 107-113, 2005.
    https://pubmed.ncbi.nlm.nih.gov/15626482/
  5. Klein SL, Flanagan KL. Sex differences in immune response. Nat Rev Immunol 16 (10): 626-638, 2016.
    https://pubmed.ncbi.nlm.nih.gov/27546235/
  6. Straub RH. The complex role of estrogens in inflammation. Endocr Rev 28(5): 521-574, 2007.
    https://pubmed.ncbi.nlm.nih.gov/17640948/
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