Sex Hormones in SARS-CoV-2 Susceptibility: Key Players or Confounders?

Overview

Journal Nat Rev Endocrinol

Specialty Endocrinology

Date 2022 Dec 9

PMID 36494595

Authors

Nicola Lott

Caroline E Gebhard

Susan Bengs

Achi Haider

Gabriela M Kuster

Vera Regitz-Zagrosek

Catherine Gebhard

Affiliations

Soon will be listed here.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

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References

Goren A, Vano-Galvan S, Wambier C, McCoy J, Gomez-Zubiaur A, Moreno-Arrones O . A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain - A potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol. 2020; 19(7):1545-1547. DOI: 10.1111/jocd.13443. View

Tukiainen T, Villani A, Yen A, Rivas M, Marshall J, Satija R . Landscape of X chromosome inactivation across human tissues. Nature. 2017; 550(7675):244-248. PMC: 5685192. DOI: 10.1038/nature24265. View

Muus C, Luecken M, Eraslan G, Sikkema L, Waghray A, Heimberg G . Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med. 2021; 27(3):546-559. PMC: 9469728. DOI: 10.1038/s41591-020-01227-z. View

Shattuck-Heidorn H, Danielsen A, Gompers A, Bruch J, Zhao H, Boulicault M . A finding of sex similarities rather than differences in COVID-19 outcomes. Nature. 2021; 597(7877):E7-E9. DOI: 10.1038/s41586-021-03644-7. View

van Zeggeren I, Boelen A, van de Beek D, Heijboer A, Vlaar A, Brouwer M . Sex steroid hormones are associated with mortality in COVID-19 patients: Level of sex hormones in severe COVID-19. Medicine (Baltimore). 2021; 100(34):e27072. PMC: 8389969. DOI: 10.1097/MD.0000000000027072. View

Aguilar-Pineda J, Albaghdadi M, Jiang W, Vera-Lopez K, Nieto-Montesinos R, Alvarez K . Structural and Functional Analysis of Female Sex Hormones against SARS-CoV-2 Cell Entry. Int J Mol Sci. 2021; 22(21). PMC: 8584232. DOI: 10.3390/ijms222111508. View

Welen K, Rosendal E, Gisslen M, Lenman A, Freyhult E, Fonseca-Rodriguez O . A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. Eur Urol. 2022; 81(3):285-293. PMC: 8673828. DOI: 10.1016/j.eururo.2021.12.013. View

Nelson C, Sama I, Codd V, Webb T, Ye S, Lang C . Genetic Associations With Plasma Angiotensin Converting Enzyme 2 Concentration: Potential Relevance to COVID-19 Risk. Circulation. 2020; 142(11):1117-1119. DOI: 10.1161/CIRCULATIONAHA.120.049007. View

Green M, Nitzan D, Schwartz N, Niv Y, Peer V . Sex differences in the case-fatality rates for COVID-19-A comparison of the age-related differences and consistency over seven countries. PLoS One. 2021; 16(4):e0250523. PMC: 8084161. DOI: 10.1371/journal.pone.0250523. View

10.

Lovre D, Bateman K, Sherman M, Fonseca V, Lefante J, Mauvais-Jarvis F . Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial. BMJ Open. 2021; 11(11):e053684. PMC: 8635865. DOI: 10.1136/bmjopen-2021-053684. View

11.

Brizzi A, Whittaker C, Servo L, Hawryluk I, Prete Jr C, de Souza W . Report 46: Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals. medRxiv. 2021; . PMC: 8575144. DOI: 10.1101/2021.11.01.21265731. View

12.

Shah S . COVID-19 and Progesterone: Part 1. SARS-CoV-2, Progesterone and its potential clinical use. Endocr Metab Sci. 2021; 5:100109. PMC: 8349425. DOI: 10.1016/j.endmts.2021.100109. View

13.

Li F, Han M, Dai P, Xu W, He J, Tao X . Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. Nat Commun. 2021; 12(1):866. PMC: 7870838. DOI: 10.1038/s41467-021-21171-x. View

14.

Galasso V, Pons V, Profeta P, Becher M, Brouard S, Foucault M . Gender differences in COVID-19 attitudes and behavior: Panel evidence from eight countries. Proc Natl Acad Sci U S A. 2020; 117(44):27285-27291. PMC: 7959517. DOI: 10.1073/pnas.2012520117. View

15.

Cadegiani F, Zimerman R, Fonseca D, Correia M, Muller M, Bet D . Final Results of a Randomized, Placebo-Controlled, Two-Arm, Parallel Clinical Trial of Proxalutamide for Hospitalized COVID-19 Patients: A Multiregional, Joint Analysis of the Proxa-Rescue AndroCoV Trial. Cureus. 2022; 13(12):e20691. PMC: 8712234. DOI: 10.7759/cureus.20691. View

16.

Nickols N, Goetz M, Graber C, Bhattacharya D, Soo Hoo G, Might M . Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized.... Trials. 2021; 22(1):431. PMC: 8256647. DOI: 10.1186/s13063-021-05389-0. View

17.

Li K, Meyerholz D, Bartlett J, McCray Jr P . The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19. mBio. 2021; 12(4):e0097021. PMC: 8406266. DOI: 10.1128/mBio.00970-21. View

18.

Schroeder M, Schaumburg B, Mueller Z, Parplys A, Jarczak D, Roedl K . High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study. Emerg Microbes Infect. 2021; 10(1):1807-1818. PMC: 8451658. DOI: 10.1080/22221751.2021.1969869. View

19.

Melgert B, Oriss T, Qi Z, Dixon-McCarthy B, Geerlings M, Hylkema M . Macrophages: regulators of sex differences in asthma?. Am J Respir Cell Mol Biol. 2009; 42(5):595-603. PMC: 2874445. DOI: 10.1165/rcmb.2009-0016OC. View

20.

Newson L, Manyonda I, Lewis R, Preissner R, Preissner S, Seeland U . Sensitive to Infection but Strong in Defense-Female Sex and the Power of Oestradiol in the COVID-19 Pandemic. Front Glob Womens Health. 2021; 2:651752. PMC: 8593953. DOI: 10.3389/fgwh.2021.651752. View