Sex differences in the relationship between digit ratio (2D:4D) and national case fatality rates for COVID-19: A reply to Sahin (2020).

Sahin [1] re-examined our finding of a positive association between national male (but not female) digit ratios (2D:4D; the relative lengths of the index and ring fingers) and case fatality rates (CFR's) for COVID-19 [2]. The re-analysis confirms the positive relationship in a more recent data set provided by the World Health Organization, suggesting that the relationship of national male 2D:4D and CFR's is temporally stable [3]. In addition, Sahin added a regional variable (EURO/Non-EURO) and a “country size” variable (number of cases) to the regression equation, and detected a negative association between female 2D:4D and CFR's. Thus, the re-analysis extends previous findings of sex differences in mortality (males > females) in the relationship between 2D:4D and national CFR's for COVID-19 [2]. It also replicates the null finding of Jones et al. [4] for an association between 2D:4D and the percent male deaths in a smaller and less reliable sample. Jones et al.'s [4] focus on this without considering the main finding of 2D:4D and national CFR's for COVID-19 had the effect of obfuscating the latter [3].

Digit ratio is sexually dimorphic (males < females) [5]. The dimorphism arises early in foetal development and does not change substantially during development [6]. Digit ratio is presumably influenced by the ratio of foetal testosterone (T) to oestrogen (E) (high T/E = low 2D:4D) [5]. A positive association between national male 2D:4D and CFR's suggest that populations of males who have experienced low prenatal T/E are prone to high COVID-19 mortality. Conversely, a negative association between national female 2D:4D and CFR's suggest that populations of females who have experienced high prenatal T/E are prone to high COVID-19 mortality. Thus, low prenatal T males and/or high prenatal T in females may account for a substantial proportion of the national differences in COVID-19 mortality.

Cardiovascular problems are co-morbidities that increase COVID-19 mortality [7]. Endogenous T in men correlates negatively with blood pressure and deaths from cardiovascular disease [8]. However, in women, endogenous T shows positive relationships with obesity and the metabolic syndrome [9]. Important in this is the control of blood pressure by angiotensin-converting enzyme (ACE) and ACE2 enzymes; the action of the former leads to vasoconstriction and the latter to vasodilation. ACE2 is the entry point into cells for SARS-CoV-2 [10]. Testosterone is necessary for this as activity of the androgen receptor and transcription of the transmembrane protease serine 2 (TMPRSS2) gene is required for SARS-CoV2 cell entry [10]. This reduces the numbers of ACE2 molecules on the cell's surface, causing an imbalance in ACE/ACE2 interaction, which in turn causes lung damage.

At the national level, the re-analysis [1] confirms a positive relationship between 2D:4D and CFR for COVID-19 in males [2] and reports a new negative relationship in females. This supports a sex difference in the relationship between 2D:4D and COVID-19 severity. At the individual level, it is important to determine whether severity of COVID-19 correlates positively with 2D:4D in men and negatively with 2D:4D in women.

Declaration of competing interest

None declared.