Abstract
In the short time since severe acute respiratory syndrome coronavirus 2 (henceforth referred to as coronavirus disease 2019 [COVID-19]) appeared, numerous articles have suggested that testosterone (T) may be a major contributor to infection and death since more men than women die, and two proteins involved in viral host entry are thought to be upregulated by androgens. We investigated whether the available data supported this supposition. A MEDLINE search was performed with keywords of COVID-19 variations and androgens or T. Data regarding COVID-19 infections and deaths were obtained from the literature, the World Health Organization, and the U.S. Center for Disease Control, GLOBAL HEALTH5050 and the Harvard School of Public Health Gender Science Laboratory. Studies with T measurements in COVID-19 patients were reviewed. Studies investigating the relationship between T and angiotensin converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS2) expression were reviewed. Global and U.S. data reveal that infection rates in men and women are similar. Men accounted for 58% and women 42% of global deaths. U.S. data revealed a ratio of 54% male deaths to 46% female deaths. However, this finding was inconsistent, as several countries reported greater numbers of female deaths, for example, Canada, Portugal, Finland, and Vietnam. In the United States, 23.5% of states and territories reported more deaths among females. Highest death rates for men and women occurred among the elderly, when serum T is at its lifetime nadir, and low death rates were observed in young adults when serum T is at its peak. All four studies reporting T measurements in COVID-19 patients indicated that low T levels were associated with adverse outcomes, that is, transfer to intensive care unit or death. Although several studies did show androgenic upregulation of TMPRSS2 and ACE2 in prostate, and cancer cell lines of prostate and lung, human and murine lung tissue fails to show a difference in expression between males and females. Observed data fail to support the popular notion that androgens contribute meaningfully to COVID-19 infection and severity of illness. On the contrary, these data raise the possibility that low T may be responsible for disease severity. There is no evidence that androgens upregulate key proteins involved with COVID-19 infection in lung. The possibility that T therapy may aid management of hospitalized COVID-19 patients merits investigation.
Highlights
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; referred to as coronavirus disease 2019 [COVID-19]) that first appeared in China in December 2019 is the most serious and widespread public health emergency of the past century
State by state data showed a similar pattern without exception, with individuals 75 years and older accounting for a large proportion of deaths, and individuals
An alternative explanation that does not involve T may be that men with advanced prostate cancer, weakened by androgen deprivation therapy (ADT), may have taken steps to avoid exposure and/or testing. In this communication we have examined the evidence regarding gender disparity with COVID-19 infections and deaths, and the scientific evidence for biological mechanisms that may implicate T in contributing to greater disease burden in men. These results provide strong evidence that higher T does not contribute to greater susceptibility to infection or deaths with COVID-19 infection
Summary
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; referred to as coronavirus disease 2019 [COVID-19]) that first appeared in China in December 2019 is the most serious and widespread public health emergency of the past century. The first epicenters for COVID-19 were China in December 2019, followed by Italy and Spain in January 2020 Initial data from these areas indicated a strong predominance of male deaths. This led to speculation that intrinsic biological differences between men and women, such as testosterone (T), may be responsible for the higher disease burden in men.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17] This speculation is widespread, as a MEDLINE search already reveals publication of an astonishing 71 articles through September 7, 2020 using key words ‘‘androgens’’ and ‘‘COVID-19.’’. As T has an unfortunate history as a bete noir in medicine, falsely believed for decades to cause prostate cancer, and more recently incorrectly associated with increased cardiovascular risk (reviewed in Morgentaler and Traish[24]). False scientific beliefs create their own radiating spheres of persistent misinformation and subsequent poor judgments, thereby creating an environment hostile to investigation of alternative possibilities
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