A Multi-hospital Study in Wuhan, China: Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection

  1. Ting Ding
  2. Jinjin Zhang
  3. Tian Wang
  4. Pengfei Cui
  5. Zhe Chen
  6. Jingjing Jiang
  7. Su Zhou
  8. Jun Dai
  9. Bo Wang
  10. Suzhen Yuan
  11. Wenqing Ma
  12. Lingwei Ma
  13. Yueguang Rong
  14. Jiang Chang
  15. Xiaoping Miao
  16. Xiangyi Ma
  17. Shixuan Wang

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Abstract

Importance

How to explain the better prognosis of female coronavirus disease 2019 (COVID-19) patients than that of males?

Objective

To determine the correlation between menstruation status/sex hormones and prognosis of COVID-19, and to identify potential protective factors for female patients.

Design, Setting, and Participants

A cross-sectional study of COVID-19 patients who were hospitalized at Tongji and Mobile Cabin Hospitals from Jan 28, 2020 to March 8, 2020.

Exposures

Confirmed SARS-CoV-2 infection.

Main Outcomes and Measures

Sex differences in severity and composite endpoints (admission to intensive care unit (ICU), use of mechanical ventilation, or death) of COVID-19 patients were compared. The correlation analysis and cox/logistic regression modeling of menstruation status/sex hormones and prognosis were conducted. Correlation between cytokines related to immunity and inflammation and disease severity or estradiol (E2) was revealed.

Results

Chi square test indicated significant differences in distribution of composite endpoints (p<0.01) and disease severity (p=0.05) between male and female patients (n=1902). 435 female COVID-19 patients with menstruation records were recruited. By the end of Mar 8, 111 patients recovered and discharged (25.3%). Multivariate Cox regression model adjusted for age and severity indicated that post-menopausal patients show the greater risk of hospitalization time than non-menopausal patients (relative hazard [RH], 1.91; 95% confidence interval [CI], 1.06-3.46) Logistic regression model showed that higher anti-müllerian hormone (AMH) as a control for age increases the risk of severity of COVID-19 (HR=0.146,95%CI = (0.026-0.824) p=0.029 ). E2 showed protective effect against disease severity (HR= 0.335, 95%CI = (0.105-1.070), p= 0.046). In the Mann-Whitney U test, the higher levels of IL6 and IL8 were found in severe group ( p= 0.040, 0.033 ). The higher levels of IL2R, IL6, IL8 and IL10 were also observed in patients with composite end points ( p<0.001, <0.001, 0.009, 0.040 ). E2 levels were negatively correlated with IL2R, IL6, IL8 and TNFα in luteal phase (Pearson Correlation=−0.592, −0.558, −0.545, −0.623; p=0.033, 0.048, 0.054, 0.023 ) and with C3 in follicular phase (Pearson Correlation=-0.651; p=0.030 ).

Conclusions and Relevance

Menopause is an independent risk factor for COVID-19. E2 and AMH are negatively correlated with COVID-19’s severity probably due to their regulation of cytokines related to immunity and inflammation.

Key Points

Question

Any differences in the outcomes between hospitalized female and male COVID-19 patients? If so, why?

Findings

Female patients display better prognosis than male patients. Non-menopausal women have shorter length of hospital stays, and AMH and E2 are negatively correlated with COVID-19’s severity. There is a negative correlation between E2 and the levels of IL6, IL8, IL2R and TNF-α, which are significantly correlated with disease severity or composite endpoint.

Meaning

Non-menopause and female sex hormones, especially E2 and AMH, are potential protective factors for females COVID-19 patients. E2 supplements could be potentially used for COVID-19 patients.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.03.26.20043943: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics and Trial Registration: This study was reviewed and approved by the Medical Ethical Committee of Tongji Hospital of Huazhong University of Science and Technology (TJ-IRB20200214).
    Consent: Oral informed consent was obtained from each enrolled patient.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variable509 female patients (441 of Tongji Hospital and 68 of Cabin Hospital) were inquired by telephone follow-up with menstrual status and gynecologic history, 435 patients were finally included.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted with SPSS software version 19.0 and R software version 3.5.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

    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.

  2. Version published to 10.1101/2020.03.26.20043943v1 on medRxiv