Aromatase, testosterone, TMPRSS2: determinants of COVID-19 severity

Abstract

Background: Male sex has been identified as a risk factor for worse COVID-19 outcomes. This sex difference has been mostly attributed to the complex role of sex hormones. Cell surface entry of SARS-CoV-2 is mediated by the transmembrane protease serine 2 (TMPRSS2) which is under transcriptional regulation by androgens. P450 aromatase enzyme converts androgens to estrogens. This study measured concentrations of aromatase enzyme, testosterone, estradiol, and TMPRSS-2 in plasma of hospitalized COVID-19 patients to elucidate the dynamics of sex-linked disparity in COVID-19 and correlate them with disease severity and mortality.

Methods: In this prospective cohort study, a total of 265 patients (41% women), age 18 years and older, who had a positive COVID-19 PCR test and were hospitalized for COVID-19 at Memorial Hermann Hospital in Houston, (between May 2020 and May 2021) were enrolled in the study if met inclusion criteria. Plasma concentrations of Testosterone, aromatase, TMPRSS-2, and estradiol were measured by ELISA. COVID-19 patients were dichotomized based on disease severity into moderate-severe (n = 146) or critical (n = 119). Mann Whitney U and logistic regression were used to correlate the analytes with disease severity and mortality.

Results: TMPRSS2 (2.5 ± 0.31 vs. 1.73 ± 0.21 ng/mL, p < 0.01) and testosterone (1.2 ± 0.1 vs. 0.44 ± 0.12 ng/mL, p < 0.01) were significantly higher in men as compared to women with COVID-19 after adjusting for age in a multivariate model. There was no sex difference seen in the level of estradiol and aromatase in COVID-19 patients. TMPRSS2 and aromatase were higher, while testosterone was lower in patients with increased COVID-19 severity. They were independently associated with COVID-19 severity, after adjusting for several baseline risk factors in a multivariate logistic regression model. In terms of mortality, TMPRRS2 and aromatase levels were significantly higher in non-survivors.

Conclusions: Our study demonstrates that testosterone, aromatase, and TMPRSS2 are markers of COVID-19 severity. Estradiol levels do not change with disease severity in COVID-19. In terms of mortality prediction, higher aromatase and TMPRSS-2 levels can be used to predict mortality from COVID-19 in hospitalized patients. COVID-19 has caused over a million deaths in the U.S., with men often getting sicker than women. Testosterone, a male hormone, helps control a protein called TMPRSS-2, which allows the COVID-19 virus to spread more easily in the body. A protein called aromatase converts the male hormone testosterone into the female hormone estrogen. It is thought that female hormone estrogen helps protect women from getting seriously ill from COVID-19. To understand the role of these hormones in COVID-19 and sex differences, we measured levels of testosterone, estrogen, aromatase (which turns testosterone into estrogen), and TMPRSS-2 in hospitalized COVID-19 patients. We also checked how this level might reflect the severity of the disease. We found that critically ill COVID-19 patients (the ones in ICU) had higher levels of TMPRSS-2 and aromatase, and lower testosterone levels. When we used these hormone levels to predict death in hospitalized COVID-19 patients, higher levels of TMPRSS-2 and aromatase were linked to a lower chance of survival.

Keywords: Aromatase; COVID-19; CRP; Sex differences.

Fig. 1

Clinical severity and Hormones: (A) Using PCA analysis, we report a panel of hormones (testosterone, TMPRSS2 and Aromatase) was able to segregate COVID-19 patients who ate at risk of severe clinical course (1-Clinical, 0-Moderate-Severe) (B) Inclusion of hormone panel (including testosterone, TMPRSS2 and Aromatase) in addition to baseline risk factors in a logistic regression model significantly imporved the prediction of severity course over the baseline model by 8.7% (0.94 ± 0.02 [95% CI: 0.88 to 0.97] vs 0.86 ± 0.03 [95% CI: 0.79 to 0.91], p<0.01, De-Long Test)

Fig. 2

Mortality and Hormones: (A) Using PCA analysis, tested the same panel of hormones (inludng testosterione, TMPRSS2, and Aromatase) used to segregate COVID-19 severity to segregate mortality among critical subjects. (B) The same panel of hormones in addition to baseline risk factors improved the prediction of mortality at admission over the baseline model by 13% (0.86 ± 0.04 [95% CI: 0.74 to 0.93] vs 0.76 ± 0.06 [95% CI: 0.63 to 0.86], p<0.01, De-Long Test