To our knowledge, this study is the first report with alargenumber of confirmed cases evaluating the effect of sex hormoneonthe clinical outcome of COVID-19. In this study, confirmedcaseswere most prevalent in young women. Older age andunderlyingcomorbidities rather than sex had a stronger associationwithmortality. HRT did not have a statistically significantassociationwith clinical outcomes in peri- and post-menopausalwomen. Thesefindings suggest that female sex hormone may not have aprotectiverole in morbidity and mortality of COVID-19.
Male dominant susceptibility to viral respiratory infectionswaspreviously suggested9,10. Several studies havereporteda male-biased sex ratio in cases confirmedwithCOVID-1911-13. In the Middle East respiratorysyndromecoronavirus (MERS-CoV) outbreak in South Korea, the numberofinfected men was higher than that of infected women (59.7%vs.40.3%)14. However, epidemiologic studies of severeacuterespiratory syndrome coronavirus (SARS-CoV) infection showedthatinfected female patients are more common inseveralcountries (55.7% in Hong Kong, 61.0% in Toronto, 66.0%inSingapore, and 63.2% in Guanzhou)15. Wealsodemonstrated that the number of patients infected withSARS-CoV-2were more common in women. In South Korea, the largestnumber ofcases of COVID-19 is associated with specificreligiousgroups1. The predominance of women in thosereligiousgroups could be reflected in the female-biased sex ratiowithin ourdomestic COVID-19 outbreak. In addition, the occupationalhazardsof a crowded workplace could be a risk factor forSARS-CoV-2infection. In South Korea, the COVID-19 outbreak emergedat a callcentre, where the workers were at a high risk of coming incontactwith each other16. In this call centre, theaffectedindividuals were predominantly women. We believe that thesesocialand cultural factors could have led to sex-specificdisparities inCOVID-19 morbidity in South Korea.
In contrast to the studies conducted in other countries,ourstudy showed that COVID-19 was most prevalent in women of the20–39age group. This finding is also seen in another study usingdatareported to the Korea Centers for Disease ControlandPrevention7,17. In 2015, the MERS-CoV outbreak inSouthKorea spread through in-hospital infections14,18.Hence,during the COVID-19 outbreak, clinicians activelyperformeddiagnostic tests to prevent in-hospital transmission. Inaddition,the Korean government established a wide range ofindications fordiagnostic testings, so that any individual wantingto be testedcan undergo the test, even if symptoms are not severe.Therefore,many healthy young adults with mild or no symptoms couldbe testedand diagnosed. Our results may represent the realepidemiology ofCOVID-19 encompassing asymptomatic to severecases.
Data from several countries showed a male-biased sex ratioinCOVID-19 mortality11,13,19. In previous micemodels,female hormones had a protective effect on mortality duetoSARS-CoV infection3. McCoy et al. suggestedthatandrogens, which could play an important role in SARS-CoV-2entryinto the host cell, seemed to be implicated inCOVID-19mortality4. However, in our study, male sex wasnot anindependent risk factor for mortality, and there wasnostatistically significant association between HRT and theclinicaloutcomes of peri- and post-menopausal women. Although ourstudy didnot corroborate a role of female hormones againstSARS-CoV-2infection, further studies, which include emerging casesacrossseveral countries, are required to determine the effect ofsexhormones during COVID-19 infection.
This study has several limitations. First, due to the natureofHIRA data, it was impossible to investigate detailedpatientinformation, such as smoking history, viral loads,laboratoryresults, and radiologic findings, which could influenceclinicaloutcomes. Second, we cannot rule out the possibilityofunderestimated number of male patients due to asymptomatic ormildinfections in COVID-19. A cohort study of patients withsubclinicalmanifestations is needed to determine the sex ratio ofentireSARS-CoV-2 infections. Third, because of the limited numberofwomen receiving HRT, we could not fully evaluate the effect ofsexhormone on clinical outcomes of COVID-19. In addition,menopausalstatus of female patients could not be evaluated.However,considering that the mean age of menopause, 49.3±0.1 years,isrelatively younger in Korea than that ofothercountries20, the patients included in subgroupanalysismay represent peri- and post-menopausal women.
In conclusion, this study may provide indirectepidemiologicevidence on the effect of female sex hormone on theprevalence andclinical outcome of COVID-19. Our report could assistin theeffective planning of valuable health care resource use andpatientmanagement during the current pandemic.