Researchers trying to understand why females infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lower mortality and better outcomes than males, analysed how biological sex differences may contribute to male-biased death in coronavirus disease 2019 (COVID-19).
Their findings, published in Clinical Infectious Diseases, suggest that anti-Müllerian hormone (AMH) and estradiol (E2) were potential protective factors, negatively correlated with COVID-19 severity, with E2 possibly exerting its effect by regulating cytokines linked to immunity and inflammation. The study also found that menopause was an independent risk factor for female COVID-19 patients.
“Our data demonstrate that sex-bias exists in COVID-19 patients, such that non-menopausal females have milder severity and better outcomes than age-matched males. The difference disappeared when [we] compared post-menopausal women with age-matched men,” said the authors, led by Ting Ding, Department of Obstetrics and Gynecology, Tongji Hospital, Wuhan, China. “Clinical research about hormone supplement is urgently needed to further verify E2’s protective and therapeutic effects on COVID-19 menopausal females, even on males,” they added.
The study recruited all confirmed patients hospitalized at three branches of Tongji Hospital (n=1902) from January 28 to March 8, 2020. Female patients were divided into non-menopause and menopause groups depending on their menstrual status, with each group also compared to age-matched males. No significant differences in comorbidities existed between the non-menopausal and menopausal females and the age-matched males.
The authors said they found no apparent differences when comparing either disease severity or clinical outcomes in menopausal females versus age-matched males (p=0.83; p=0.49, respectively). However, they said “obvious differences” emerged when looking at non-menopausal females and age-matched males. Among these, a total of 200 patients suffered severe disease, including 76 non-menopausal females and 124 age-matched males (p<0.01). Further, none of the non-menopausal females died, compared with 16 deaths among the age-matched males (p<0.01).
The study also assessed differences in menstruation in relation to severity and a composite clinical outcome (ICU admission, or ventilation or death) in 435 female patients who were younger than 60. The median age was 49 years (IQR, 38-56), and for patients above 55 years of age, the proportion was significantly increased in the severe group (p<0.0012).
Results from a multivariate Cox regression analysis showed that non-menopausal patients tended to have a lower hospitalization proportion, and to be discharged earlier than menopausal patients, controlling for age and severity (hazard ratio [HR]= 1.91; 95% confidence interval [CI], 1.06 – 3.46); p=0.033).
Finally, among the same group of 435 patients, researchers examined the relationship between COVID-19 severity and female sex hormones (78 women younger than 60 years of age) or serum cytokine levels (263 women).
Both AMH and E2 showed a negative correlation with severity of infection (AHR=0.146/0.304, 95%CI = [0.026-0.824]/[0.092-1.001], p=0.029/0.05). E2 levels were also negatively correlated with IL-2R, IL-6, IL-8 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).
“Estrogens are thought to protect non-menopausal women from hepatitis C virus and other pathogens. Also, ovariectomized and estrogen-receptor antagonist-treated female mice were more susceptible to SARS-CoV, which may be due to the protective effects of estrogen receptor signaling in SARS-CoV infection. Here E2 might show the same protective pathway on SARS-CoV-2 infection, but further clinical studies are needed to verify the intrinsic mechanism,” the authors said.
They added that “E2 may be a protective factor for female COVID -19 patients by regulating cytokines or immunoproteins such as IL2R, IL6, IL8, TNFα and C3,” but in females, “severity of symptoms and outcomes may change during times of hormone fluctuation, which needs to be validated prospectively.”
The authors noted that while E2 was negatively correlated with COVID-19 severity in this study, the causal relationship between them remains unclear. They also noted that as serum E2 levels were based on only one blood sample per patient, regardless of phase of menstrual cycle, and not collected before the SARS CoV-2 infection, “the results may not completely reflect the average E2 level and its effects.”