Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

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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.

Abstract

There is growing awareness of differences in susceptibility to SARS-CoV-2 infection and COVID-19 severity between men and women. This Review assesses the evidence for this disparity and its potential causes, with a focus on the role of sex hormones.

Key points

There is currently no clear evidence that a sex-specific expression of virus entry receptors accounts for some of the sex discordances observed in coronavirus disease 2019 (COVID-19).
Studies on the effects of oestrogen, progesterone and testosterone on the course of COVID-19 have provided inconsistent results, and current data do not support the administration of oestradiol or deprivation of androgens in COVID-19 treatment.
Much more research is needed to clarify the potential therapeutic value of endogenous or exogenous sex hormones in COVID-19.

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Most cited references 165

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)

Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

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Author and article information

Contributors

Catherine Gebhard:

ORCID: http://orcid.org/0000-0001-7240-5822

catherine.gebhard@usz.ch

Journal

Journal ID (nlm-ta): Nat Rev Endocrinol

Journal ID (iso-abbrev): Nat Rev Endocrinol

Title: Nature Reviews. Endocrinology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1759-5029

ISSN (Electronic): 1759-5037

Publication date (Electronic): 9 December 2022

Pages: 1-15

Affiliations

[1 ]GRID grid.412004.3, ISNI 0000 0004 0478 9977, Department of Nuclear Medicine, , University Hospital Zurich, ; Zurich, Switzerland

[2 ]GRID grid.7400.3, ISNI 0000 0004 1937 0650, Center for Molecular Cardiology, , University of Zurich, ; Schlieren, Switzerland

[3 ]GRID grid.410567.1, Intensive Care Unit, , University Hospital Basel, ; Basel, Switzerland

[4 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Division of Nuclear Medicine and Molecular Imaging, , Massachusetts General Hospital, ; Boston, MA USA

[5 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Radiology, , Harvard Medical School, ; Boston, MA USA

[6 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Department of Cardiology and Department of Biomedicine, , University Hospital and University of Basel, ; Basel, Switzerland

[7 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Charité, Universitätsmedizin Berlin, ; Berlin, Germany

[8 ]GRID grid.452396.f, ISNI 0000 0004 5937 5237, DZHK (German Centre for Cardiovascular Research), partner site Berlin, ; Berlin, Germany

[9 ]GRID grid.411656.1, ISNI 0000 0004 0479 0855, Department of Cardiology, , Inselspital Bern University Hospital, ; Bern, Switzerland

Author information

Ahmed Haider http://orcid.org/0000-0002-5204-4473

Vera Regitz-Zagrosek http://orcid.org/0000-0002-3566-3467

Catherine Gebhard http://orcid.org/0000-0001-7240-5822

Article

Publisher ID: 780

DOI: 10.1038/s41574-022-00780-6

PMC ID: 9734735

PubMed ID: 36494595

SO-VID: 8c536bba-e6bb-4cbe-bc43-49b727f0c96b

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

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Novel Coronavirus Disease COVID-19

Most cited references 165

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

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