madman
Super Moderator
ABSTRACT
COVID-19 consistently displays higher mortality in males. This sex-specific difference in outcomes is seen not only in the current COVID-19 pandemic but also in prior viral epidemics and pandemics. Sex hormones, such as testosterone, play a clear role in modulating the immune response, providing a clue that may illuminate the underpinnings of these outcomes. Developing a deeper understanding of these epidemiological findings permits a more effective response to the disease. This article summarizes the sex-specific COVID-19 outcomes, the role of androgens in generating these outcomes, and the potential role of modifying testosterone levels as a form of treatment of COVID-19.
INTRODUCTION
COVID-19, a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread worldwide. Many countries affected by the COVID-19 pandemic is seeing worse clinical outcomes in males than in females.1 This pattern of outcomes was also seen in prior coronavirus epidemics, including the severe acute respiratory distress (SARS) and Middle East respiratory syndrome (MERS) coronavirus epidemics.2,3 These sex-specific outcomes of viral pandemics are not limited to the 21st century, with the 1918 influenza pandemic resulting in higher mortality in males than in females in the United States.4 Sex hormones, such as testosterone and estrogen, are a defining driver of the physiologic distinctions between males and females and likely play a role in the observed pattern of outcomes in COVID-19. Testosterone has complex effects on the immune system, introducing an essential question of how varied levels of testosterone might influence COVID-19 in males. Developing a better understanding of testosterone’s influence on COVID-19 will provide more clarity in the broader public health approach to the disease. This review explores the sex differences in COVID-19 outcomes, the potential role of testosterone in driving such differences, and the implied utility of modulating testosterone levels in the treatment of COVID-19.
*SEX OUTCOME DIFFERENCES IN COVID-19
*MECHANISMS OF ANDROGEN MODULATION IN COVID-19
Regulation of Viral Entry and Fusion
Influence on the Immune Response
*THE POTENTIAL ROLE OF EXOGENOUS TESTOSTERONE
The role of testosterone in mitigating the inflammatory response has spurred interest in testosterone therapy in SARS-CoV-2 infections.47 Several studies show that the proinflammatory state that arises due to low testosterone can be suppressed with the provision of exogenous testosterone.48-50 More specifically, testosterone therapy suppresses typical inflammatory factors such as IL-1, IL-6, and TNF-a. 50 Evidence also suggests that testosterone therapy may confer a certain advantage over corticosteroids by blunting the inflammatory response to SARS-CoV-2, but without hindering the cellular immune response to the virus, as might be the case with steroid use.51 The use of testosterone in patients with chronic obstructive pulmonary disease (COPD) provides a useful analog in which to investigate its potential therapeutic role. Importantly, men with COPD have worse outcomes when infected with SARS-CoV-2.52 Studies indicate that testosterone replacement enhances lung function in middle-aged and elderly men with COPD, slowing disease progression and reducing hospitalizations compared to men with COPD not treated with testosterone replacement therapy.53 Low testosterone levels reduce respiratory muscle activity and exercise capacity,54 while normal testosterone levels show a protective effect on various respiratory parameters, such as forced expiratory volume and forced vital capacity.55 Given these findings, Caminiti et al conducted a randomized controlled trial and found that testosterone replacement therapy improved peak oxygen consumption and respiratory function,56 indicating a potential role for testosterone replacement therapy in protecting lung function in men with SARS-CoV-2. Further research on the specific use of testosterone replacement therapy in SARS-CoV-2 patients are needed to accurately assess its efficacy in this context, including age-stratified studies as well as investigations to illuminate the ideal timing and dosage of testosterone provision.
COVID-19 consistently displays higher mortality in males. This sex-specific difference in outcomes is seen not only in the current COVID-19 pandemic but also in prior viral epidemics and pandemics. Sex hormones, such as testosterone, play a clear role in modulating the immune response, providing a clue that may illuminate the underpinnings of these outcomes. Developing a deeper understanding of these epidemiological findings permits a more effective response to the disease. This article summarizes the sex-specific COVID-19 outcomes, the role of androgens in generating these outcomes, and the potential role of modifying testosterone levels as a form of treatment of COVID-19.
INTRODUCTION
COVID-19, a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread worldwide. Many countries affected by the COVID-19 pandemic is seeing worse clinical outcomes in males than in females.1 This pattern of outcomes was also seen in prior coronavirus epidemics, including the severe acute respiratory distress (SARS) and Middle East respiratory syndrome (MERS) coronavirus epidemics.2,3 These sex-specific outcomes of viral pandemics are not limited to the 21st century, with the 1918 influenza pandemic resulting in higher mortality in males than in females in the United States.4 Sex hormones, such as testosterone and estrogen, are a defining driver of the physiologic distinctions between males and females and likely play a role in the observed pattern of outcomes in COVID-19. Testosterone has complex effects on the immune system, introducing an essential question of how varied levels of testosterone might influence COVID-19 in males. Developing a better understanding of testosterone’s influence on COVID-19 will provide more clarity in the broader public health approach to the disease. This review explores the sex differences in COVID-19 outcomes, the potential role of testosterone in driving such differences, and the implied utility of modulating testosterone levels in the treatment of COVID-19.
*SEX OUTCOME DIFFERENCES IN COVID-19
*MECHANISMS OF ANDROGEN MODULATION IN COVID-19
Regulation of Viral Entry and Fusion
Influence on the Immune Response
*THE POTENTIAL ROLE OF EXOGENOUS TESTOSTERONE
The role of testosterone in mitigating the inflammatory response has spurred interest in testosterone therapy in SARS-CoV-2 infections.47 Several studies show that the proinflammatory state that arises due to low testosterone can be suppressed with the provision of exogenous testosterone.48-50 More specifically, testosterone therapy suppresses typical inflammatory factors such as IL-1, IL-6, and TNF-a. 50 Evidence also suggests that testosterone therapy may confer a certain advantage over corticosteroids by blunting the inflammatory response to SARS-CoV-2, but without hindering the cellular immune response to the virus, as might be the case with steroid use.51 The use of testosterone in patients with chronic obstructive pulmonary disease (COPD) provides a useful analog in which to investigate its potential therapeutic role. Importantly, men with COPD have worse outcomes when infected with SARS-CoV-2.52 Studies indicate that testosterone replacement enhances lung function in middle-aged and elderly men with COPD, slowing disease progression and reducing hospitalizations compared to men with COPD not treated with testosterone replacement therapy.53 Low testosterone levels reduce respiratory muscle activity and exercise capacity,54 while normal testosterone levels show a protective effect on various respiratory parameters, such as forced expiratory volume and forced vital capacity.55 Given these findings, Caminiti et al conducted a randomized controlled trial and found that testosterone replacement therapy improved peak oxygen consumption and respiratory function,56 indicating a potential role for testosterone replacement therapy in protecting lung function in men with SARS-CoV-2. Further research on the specific use of testosterone replacement therapy in SARS-CoV-2 patients are needed to accurately assess its efficacy in this context, including age-stratified studies as well as investigations to illuminate the ideal timing and dosage of testosterone provision.
