Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients

  1. Emily Toscano-Guerra
  2. Mónica Martínez-Gallo
  3. Iria Arrese-Muñoz
  4. Anna Giné
  5. Noelia Díaz-Troyano
  6. Pablo Gabriel-Medina
  7. Mar Riveiro-Barciela
  8. Moisés Labrador-Horrillo
  9. Fernando Martinez-Valle
  10. Adrián Sánchez Montalvá
  11. Manuel Hernández-González
  12. Ricardo Pujol Borrell
  13. Francisco Rodríguez-Frias
  14. Roser Ferrer
  15. Timothy M. Thomson
  16. Rosanna Paciucci

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Abstract

Background

SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients.

Methods

Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome.

Results

We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes.

Conclusions

Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications.

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  1. Version published to 10.1186/s12916-022-02345-w
  2. Version published to 10.1101/2021.06.29.21259693v3 on medRxiv
  3. Version published to 10.1101/2021.06.29.21259693v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.06.29.21259693: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The present study was performed with surplus serum samples from routinely tested hospitalized COVID-19 patients, following a protocol reviewed and approved by the Hospital Vall d’Hebron Institutional Review Board (Medical Research Ethics Committee, protocol number PR(AG)329-2020).
    Field Sample Permit: Immuno-phenotyping: Blood was collected in vacutainer tubes containing ethylene-diamine-tetra-acetic acid (EDTA) as anticoagulant (BD-Plymouth, PL6 7BP, UK) and processed within 4 h after collection.
    Sex as a biological variableStudy design: We studied a group of patients with COVID-19 (249 men and 248 women) admitted at the Vall d’Hebron Hospital between May 1st through June 30th 2020.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    ROC curves were calculated with the logistic regression model implemented in STATA 14 and the EasyROC web tool (http://www.biosoft.hacettepe.edu.tr/easyROC/), Odd Ratios (OR) were calculated by transforming areas under the curve (AUC) with the Effect Size Converter web tool (https://www.escal.site/).
    STATA
    suggested: (Stata, RRID:SCR_012763)
    Principal Component Analysis (PCA), multivariate correlation analysis and other calculations, as well as graphic representations, were performed with GraphPad Prism 9.0.2.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The limitations of our study include its observational nature on retrospective patients and samples, which has precluded the collection of samples at precisely equivalent time points after symptom onset for all patients. This has most notably impacted longitudinal studies of immune populations which, in the present study, was limited to two temporally separate determinations per male patient studied. A follow-up study is currently ongoing aimed at expanding the present study in this regard, including longitudinal analyses in women. On the other hand, several hypotheses laid out here would require formal testing by means of approaches that are not addressed in the present study. For example, the various mechanisms postulated to explain the depletion of circulating differentiated effector T cells in lethal COVID-19 patients would benefit from additional analyses of senescent and activation states of such populations with appropriate markers, as well as detailed analyses of viral infection and immune cell populations infiltrating key tissues, mainly lung and testis. Finally, pre-clinical animal models would be required for a robust experimental demonstration of mechanistic relationships between testosterone status (e. g., deprivation and replacement) and SARS-CoV-2 infection outcomes, which should also contemplate factors such as age.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2021.06.29.21259693v1 on medRxiv