5α-reductase inhibitors help reduce SARS-CoV-2 infection risk in men

Use of 5α-reductase inhibitors (5ARIs) appears to lower the risk of community-acquired infection with SARS-CoV-2 in men without prostate cancer, according to a study, noting that treatment with this drug class can help ease the burden of COVID-19.

“The physiological mechanisms underlying this association remains to be elucidated but could be related to oestradiol-associated pro-immune effects and inhibition of the angiotensin-converting enzyme 2 virus coreceptor,” the researchers said.

This study included a total of 60,474 men in a prospective registry of people tested for SARS-CoV-2 between 8 March 2020 and 15 February 2021. Participants were matched 1:1 to non-5ARI users using a matched cohort design. The researchers then completed an independent analysis for validation using unconditional logistic regression on the entire unmatched data set. Their outcome measures were the association of 5ARI use on rates of SARS-CoV-2 positivity and disease severity.

Of the men, 1,079 (1.8 percent) reported using 5ARI, and 55,100 were available for matching. The final matched cohorts consisted of 944 participants each. Mean use duration was 60.4 months (interquartile range 17‒84 months). [J Urol 2022;207:183-189]

Users of 5ARI had significantly lower absolute risk for infection compared to nonusers (42.3 percent vs 47.2 percent, respectively; absolute risk reduction [ARR], 4.9 percent; odds ratio [OR], 0.81, 95 percent confidence interval [CI], 0.67‒0.97; p=0.026).

The protective benefit of 5ARI use was substantiated by unconditional multivariable logistic regression analysis of the entire cohort (ARR, 5.3 percent; OR, 0.877, 95 percent CI, 0.774‒0.995; p=0.042). Of note, use of 5ARI did not correlate with disease severity.

“In the absence of detailed physiological and immunological data from patients using 5ARIs, we can only speculate on the mechanism by which inhibition of 5α-reductase protects against SARS-CoV-2 infection,” the researchers said. “Although 5ARIs are sometimes classified as antiandrogens, their use results in an increase in serum testosterone levels.”

5ARIs increase not just testosterone levels but also androstenedione. It is likely that the inhibition of 5α-reductase allows such precursors to produce more oestrogens, which have pro-immune effects and are thought to be responsible for decreasing SARS-CoV-2‒related disease severity in women. [Am J Physiol Endocrinol Metab 2006;290:856-863; N Engl J Med 2020;382:1663-1665; Am J Physiol Heart Circ Physiol 2021;320:H296-H304; Proc Natl Acad Sci U S A 2011;108:13728-13733]

“The SARS-CoV-2 pandemic has ravaged the world with a marked disproportionate impact on men,” the researchers said. “While infection rates are similar between men and women, studies have consistently shown that men experience more severe disease and higher mortality compared to women.” [Nat Commun 2020;11:6317; N Engl J Med 2020;382:1708-1720; N Engl J Med 2020;382:2372-2374]

Several explanations have been suggested for this phenomenon, one of which is the innate differences in the female immune response, which is more rapid and aggressive compared to that of men. This is supported by observations that oestradiol boosts both cellular and antibody responses to infections. [Nat Rev Immunol 2016;16:626-638; Genes Immun 2009;10:509-516; Front Immunol 2021;12:659339]