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

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.