Abstract
Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition. To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity. This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs). Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized). Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways. Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = -0.43; 95% CI, -0.52 to -0.17; P < .001), C-reactive protein (β = -0.38; 95% CI, -0.78 to -0.16; P = .004), interleukin 1 receptor antagonist (β = -0.29; 95% CI, -0.64 to -0.06; P = .02), hepatocyte growth factor (β = -0.46; 95% CI, -0.69 to -0.25; P < .001), and interferon γ-inducible protein 10 (β = -0.32; 95% CI, -0.62 to -0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16- (ie, classical) monocytes and CD14-CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not. In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.
Highlights
Coronaviral diseases have constituted a major public health issue during the last 2 decades, starting with the severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic in 2002 through 2003,1 continuing with the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in 2012,2 and most recently, the current COVID-19 pandemic
Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = −0.43; 95% CI, −0.52 to −0.17; P < .001), C-reactive protein (β = −0.38; 95% CI, −0.78 to −0.16; P = .004), interleukin 1 receptor antagonist (β = −0.29; 95% CI, −0.64 to −0.06; P = .02), hepatocyte growth factor (β = −0.46; 95% CI, −0.69 to −0.25; P < .001), and interferon γ–inducible protein 10 (β = −0.32; 95% CI, −0.62 to −0.10; P = .007)
Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16− monocytes and CD14−CD16+ monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not. In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease
Summary
Coronaviral diseases have constituted a major public health issue during the last 2 decades, starting with the severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic in 2002 through 2003,1 continuing with the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in 2012,2 and most recently, the current COVID-19 pandemic. Patients hospitalized with COVID-19 are more likely to be men than women.. Patients hospitalized with COVID-19 are more likely to be men than women.3 This sexual dimorphism has led some to presume that the male sex hormone, testosterone, may be a risk factor associated with the severity of COVID-19 and that estrogen may be protective.. Obesity, metabolic syndrome, and many chronic illnesses, such as type 2 diabetes, renal insufficiency, and chronic lung disease, are associated with lower serum testosterone concentrations in men.. Studies among patients in the hospital, including those with COVID-19, have found that testosterone concentrations are lower in men requiring intensive care unit (ICU) admission or use of ventilators than in those with milder illness.. We conducted a detailed investigation into the association of testosterone with disease severity and inflammation in patients with COVID-19
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