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. 2021 May 3;4(5):e2111398.
doi: 10.1001/jamanetworkopen.2021.11398.

Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19

Sandeep Dhindsa  1 , Nan Zhang  2 , Michael J McPhaul  3 , Zengru Wu  3 , Amit K Ghoshal  4 , Emma C Erlich  2 , Kartik Mani  5   6   7 , Gwendalyn J Randolph  2 , John R Edwards  8 , Philip A Mudd  9 , Abhinav Diwan  5   6   7   10   11
Affiliations

Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19

Sandeep Dhindsa et al. JAMA Netw Open. .

Abstract

Importance: Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition.

Objective: 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.

Design, setting, and participants: 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).

Exposures: 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).

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Diwan reported receiving consulting fees from ERT. Dr Dhindsa reporting receiving consulting fees from Bayer, Clarus Therapeutics, and Acerus Pharmaceuticals. Dr McPhaul reported serving as a full-time employee for Quest Diagnostics during the conduct of the study. Dr Ghoshal reported receiving stock options and restricted shares from Quest Diagnostics. Dr Erlich reported receiving a grant from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study. Dr Mani reported receiving grants from the Washington University School of Medicine in St Louis Diabetes Research Center and John Cochran Veterans Hospital and serving as an employee of the Department of Veterans Affairs outside the submitted work. Dr Mudd reported receiving grants from the Foundation for Barnes-Jewish Hospital and Washington University in St Louis Institute of Clinical and Translational Science during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Testosterone Concentration in Men
The population included 24 men who never had severe COVID-19, 31 men who had severe COVID-19 at presentation to the hospital, and 35 men who developed severe COVID-19 during their hospital stay. No patient remained hospitalized beyond 7 days in the group that never had severe COVID-19. aMedian (interquartile range) testosterone concentrations of men who never had severe COVID-19 were significantly higher than those of men in the other groups at day 0, day 3, and day 7.
Figure 2.
Figure 2.. Transcriptional Profiling of Circulating Mononuclear Cells
Gene set enrichment analyses were conducted on RNA sequencing data sets from sorted cells based on CD14 and CD16 expression from 7 men with COVID-19 requiring intensive care unit treatment vs 5 men with mild disease. The x axes indicate ranked gene lists (genes are ranked by the sign of the fold change × the −log 10 of the P value); colors on the y axes, heat maps of the genes in the gene set (the range of colors [ie, red, pink, light blue, and dark blue] shows the range of the ranking metric [ie, high, moderate, low, and lowest]).
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