Little is known about the relationship between menopausal status and COVID-19 outcomes. To our knowledge, this is the first study comparing COVID-19 outcomes of premenopausal women and postmenopausal women with men for in hospitalized patients based on well-conducted propensity score-matching analysis. In this study, we observed that men were significantly more likely to experience severe disease compared to premenopausal women; however, the odds of experiencing mortality was not significantly different between the two groups. Notably, the odds of experiencing severe disease and mortality were not significantly different between men and postmenopausal women. This data suggests that menopausal status bias exists in patients with COVID-19. Considering the serious health consequences and tremendous economic impacts caused by COVID-19, our findings may be useful for guiding clinicians to deploy aggressive treatment against the poor-prognosis of postmenopausal women in clinical practice.
A recent retrospective study  reported that men were significantly associated with a higher intensive care unit (ICU) admission rate compared with women in Metropolitan Detroit. However, in this study the patients in the ICU were more likely to present with severe COVID-19 and be of older age (age >60 years) compared with patients in the general wards. In a number of studies, the poor outcomes of older patients have been associated with reduced immune system status [19-22]. Additionally, the high proportion of cases and hospitalizations observed in women might negatively affect family structure and increase health risks, and resulted in a worse prognostic profile. Jin et al  also reported a high risk of severe outcomes among men with COVID-19 in China. However, this study included only a case series of 43 patients for severity analysis due to the unavailability of detailed patient information in the public data set. In addition, this smaller study for mortality analysis analyzed a heterogeneous data set. Previously published meta-analyses [23, 24] demonstrated that men had a higher prevalence of COVID-19, a higher risk of developing severe disease, and higher mortality than women. However, the clinical characteristics between the groups were unbalanced, which may have biased the results. Omar et al  included 88 adult patients in Eastern Sudan and indicated that there was no significant difference in the death rate between men and women. However, this analysis was based on a small number of heterogeneous patients. Moreover, this study did not adjust for potential confounding factors such as age, BMI, comorbidities, or treatment, which were well balanced in our study by using propensity score-matching analysis. Collectively, these studies may be biased in a number of ways. Firstly, they comprise relatively small sample sizes, which may result in an elevated false discovery rate or even false-positive results . Secondly, the clinical characteristics between the groups were unadjusted, which was easily biased. Besides, clinical outcomes based on menopausal status were not examined in their studies. An additional limitation shared by the previous studies is that information on patient BMI and treatment medication, both known prognostic factors for COVID-19 outcomes, were not available. By contrast, in our study, BMI and treatment medication were well balanced between male and female patients. In our study, which is based on a relatively large sample size, accurate baseline and complete clinical outcome data, and propensity score-matching analysis of patients’ clinical characteristics, we demonstrated that men had a significantly higher risk of developing severe COVID-19 disease than premenopausal women, but not postmenopausal women. Our results may be explained in part by the changing biochemistry due to menopause. First, loss of ovarian function at menopause and the resulting change in the concentration of sex hormones may contribute to the increased risk of COVID-19. For example, premenopausal women have higher levels of estrogen postmenopausal women of the same age . Given that estrogen plays a crucial role in protecting female mice from SARS-CoV infection, and that ovariectomy or estrogen receptor blockage increases the susceptibility to infection and mortality , our results may be explained in part by the protective effect of estrogen against COVID-19 in premenopausal women. On the one hand, cytokine storm syndrome—an aberrant immune response to SARS-CoV-2—is one of the main reasons for the morbidity and mortality in COVID-19 . In addition to its immunomodulatory effects, estrogen modulates the expression of Th1 and Th2 cytokines, deactivates excessive inflammatory processes, and restores homeostatic conditions, thus potentially inhibiting cytokine storm syndrome from occurring in women [13, 29]. On the other hand, in vitro data suggest that estrogen might exert direct antiviral activity on SARS-CoV-2 by downregulating the expression of angiotensin converting enzyme 2 (ACE2) mRNA in bronchial epithelial cells, which has been proven to be the major receptor responsible for mediating virus entry into cells . In support of this, the data from SARS-CoV-2 indicate that the use of estrogen therapy could be effective in the fight against COVID-19 [27, 31], further emphasizing the necessity of further research in patients treated with these agents. However, whether the protective effects of estrogen on COVID-19 outcomes is dose-dependent is unclear due to the unavailability of the concentration of sex hormones in the retrospective study. Second, Honour et al reported that postmenopausal women have higher concentrations of cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and C-reactive protein, compared with premenopausal women . Zhu et al indicated that high levels of IL-6 and C-reactive protein were independent risk factors of COVID-19 severity . Akbari et al also demonstrated that group of patients with severe COVID-19 had a significant increase in the TNF-α, IL-6, and C-reactive protein compared to the non-severe group, suggesting that these cytokines were closely associated with COVID-19 severity . Hence, an increase in the concentrations of these cytokines in postmenopausal women may contribute to our findings, further emphasizing a need for increased awareness and careful monitoring of postmenopausal women. Notably, our analysis found that the mortality did not differ between the groups of men and premenopausal women, partly due to the low mortality rate observed in the limited number of premenopausal patients analyzed. However, these results should be interpreted cautiously due to the wide confidence intervals for the calculated ORs in those patients.
The present study may suffer from several limitations. First, because of the rapid emergency of the COVID-19 outbreak, our study was a retrospective analysis and not all laboratory tests were performed in all patients. Although clinical characteristics and laboratory tests were generally balanced between the men and women groups, several potentially confounding factors may not have been included and their role might be underestimated in our study. Second, the concentrations of sex hormones were unavailable due to the retrospective study design. As more data becomes available, further investigation will be required to confirm our findings. Third, the results of several clinical characteristics in our study may differ from studies in western cultures, possibly restricting the generalizability of the results. For example, previous studies mentioned that obesity (BMI>30) was an important factor for COVID-19 outcomes; there were few individuals who were obese in the present study, compared to a significantly higher number in western cultures. Finally, the separate long-term effects of COVID-19 remains unclear and needs to be evaluated further.
Perspective and significance
Menopausal status can influence COVID-19 outcomes. Premenopausal women display lower disease severity than men, while postmenopausal women do not. Physicians should take consideration of whether women are pre- or postmenopausal when they present with COVID-19 infections, and be most aggressive in their treatment of postmenopausal women similar to their treatment of men. Further mechanistic insights are needed to determine whether menopausal status has a specific impact on the immune system response to SARS-CoV-2.