Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19

Abstract

Androgens play a fundamental role in the morbidity and mortality of COVID-19, inducing both the ACE-2 receptor to which SARS-CoV-2 binds to gain entry into the cell, and TMPRS22, the transmembrane protease that primes the viral spike protein for efficient infection. The United States stands alone among developed nations in permitting one androgen, oral dehydroepiandrosterone (DHEA), to be freely available OTC and online as a “dietary supplement.” DHEA is widely used by males in the US to offset the age-related decline in circulating androgens. This fact may contribute to the disparate statistics of COVID-19 morbidity and mortality in this country. In regulatory antithesis, every other developed nation regulates DHEA as a controlled substance. DHEA is an extremely potent inhibitor of Glucose-6-phosphate Dehydrogenase (G6PD), with uniquely unstable uncompetitive inhibition kinetics. This has particular relevance to COVID-19, because G6PD-deficient human cells have been demonstrated to be exceptionally sensitive to infection by human coronavirus. Because DHEA is lipophilic and freely passes into cells, oral DHEA bypasses the normal controls regulating androgen biology and uncompetitive G6PD inhibition. DHEA’s status as a “dietary supplement” means that no clinical trials demonstrating safety have been performed, and, in the absence of physician supervision, no data on adverse events has been collected. During the current pandemic, the unrestricted availability of oral DHEA as a “dietary supplement” cannot be considered safe without proof from placebo-controlled clinical trials that it is not contributing to the severity of COVID-19. US physicians may therefore wish to query their patients’ use of DHEA.

Sexual dimorphism in COVID-19: potential clinical and public health implications

“…Placebo-controlled studies are required to investigate the use of DHEA in elderly men in the context of COVID-19. 85 Due to sustained high concentrations of oestrogens during gestation, maternal outcomes in pregnant women with COVID-19 were analysed in a systematic review and meta-analysis based on data from 24 articles including 1100 pregnancies. 86 The authors concluded that pregnancy itself does not substantially affect maternal and neonatal outcomes; however, patient numbers were low, especially considering that pregnant women are usually of younger age without specific comorbidities.…”

“…Placebo-controlled studies are required to investigate the use of DHEA in elderly men in the context of COVID-19. 85 …”

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection

“…Reduction of the activity of G6PD facilitates infection of human cells by the coronavirus. Uncompetitive inhibition of G6PD by oral dehydroepiandrosterone in endothelial cells leads to the depletion of intracellular NADPH, and the loss of NADPH depletes BH 4 , uncouples eNOS, and forms NO, highly reactive peroxide, and peroxynitrate [39].…”

Roles of steroid receptors in the lung and COVID-19

“…Given that men with higher levels of circulating androgens appear to have greater risk of severe COVID-19 symptoms [ 61–64 ], a converse cohort of patients to be investigated further are men who receive the weak adrenal androgen dehydroepiandrosterone (DHEA) as a means of counteracting low serum testosterone levels, to determine whether this affects COVID-19 infections and severity [ 83 ]. Initial population studies, undertaken when the disease first swept through Italy, indicated that in prostate cancer patients, those patients taking anti-androgen therapy had lower infection rates and lower risk of hospitalisation [ 84 ].…”