A growing body of evidence has demonstrated higher age, male sex and medical comorbidity as risk factors for COVID-19 mortality [1]. In particular, male sex, and older age were found to be significant determinants for severe SARS-CoV-2 phenotype supporting the hypothesis that hormonal constitution may be an etiology for both COVID-19 susceptibility and acute respiratory distress syndrome (ARDS) development. Moreover, differences between male and female immune responses is well known establishing that genetics and sex hormones are important for the immunogenic sex-bias [2]. Higher serum total testosterone (TT) levels are associated with an immunosuppressive role on different components of the immune cell-mediated response [3]. Pozzilli et al [4] hypothesized a role for TT in the clinical course of the SARS-CoV-2 leading to multiorgan failure.
We aimed to evaluate whether serum TT levels among a cohort of twenty-nine COVID-19 men at the time of hospital admission were associated with severity of illness (i.e. requiring an invasive oxygenation strategy) and may allow for patient monitoring and predict disease outcome. This retrospective study received formal Institutional Review Board approval.
Patients' haemato-chemical and clinical characteristics are reported in Table 1. After adjusting for Age-adjusted Charlson Comorbidity Index (ACCI), history of hypertension, dyslipidemia and smoking status, higher serum TT levels (ng/mL) were found independently associated with a lower odd of invasive oxygenation (Odds ratio [OR]: 0.43, 95%CI: 0.23-0.85; p=0.016). In addition, linear regression was used to examine the correlation between serum TT and haemato-chemical variables of interest. A significant negative correlation was found between TT and C-reactive protein (CRP), pH, Interleukine-6 (IL-6) and D-Dimer. Of note, a significant positive correlation was established among TT levels and Monocytes (x109/L) (Fig. 1A). Additionally, one-way ANOVA was used to test the differences between continuous TT and IL-6 values for the different respiratory assistance strategies confirming as thresholds of interest < 3.5-4 ng/mL for impaired T while identifying > 50 pg/mL for significantly elevated IL-6 (Fig. 1B). Locally weighted scatter-plot smoother (LOWESS) function was used to graphically depict the relationship concerning these two variables and the probability of their mutual interaction for the previously defined thresholds (Fig. 1C).
Male hypogonadism is typically of the aging male. Nevertheless, in our cohort, while age was not associated with need for O2 assistance (p=0.082), TT levels were significantly lower in the ARDS group (p=0.003) and associated with worse clinical COVID-19 phenotype. Additionally, considering the observed inverse relationship between IL-6 and TT levels, we speculate that greater TT levels could serve as hormonal shield against the COVID-19 related cytokine syndrome. Similarly, low TT levels may allow the viral infection due to a loss of immunosuppressive effect of TT. Our results are in line with the recently reported experience by Rastrelli et al [5]. In addition, we were able to identify serum TT levels at hospital admission as a potential biomarker for the requirement for invasive respiratory assistance.
Certain limitations warrant mention. First, the retrospective design and limited sample size expose the current analysis to bias and the role of chance. However, given that testicular parenchyma was recently found as a potential target of SARS-CoV-2 infection [6], we might possibly postulate Leydig cells involvement with subsequent TT levels impairment in the etiopathogenesis of the more severe ARDS cases. Moreover, our data allowed us only to make implications on the clinical severity at hospital admission but not to better define the role of TT in later history of the disease. While promising, the interplay between TT levels and COVID-19 require additional study to determine the utility of TT in clinical practice.