ABSTRACT
Background
Men who contract coronavirus disease 2019 (COVID-19) appear to have worse clinical outcomes compared with women which raises the possibility of androgen-dependent effects.
Aim
We sought to determine if testosterone replacement therapy (TRT) is associated with worse clinical outcomes.
Methods
Through a retrospective chart review, we identified 32 men diagnosed with COVID-19 and on TRT. They were propensity score matched to 63 men diagnosed with COVID-19 and not on TRT. Data regarding comorbidities and endpoints such as hospital admission, intensive care unit admission, ventilator utilization, thromboembolic events, and death were extracted. Chi-square and Kruskal-Wallis tests examined differences in categorical and continuous variables, respectively. Logistic regression analysis tested the relationship between TRT status and the study endpoints.
Results
There were no statistically significant differences between the 2 groups, and TRT was not a predictor of any of the endpoints on multivariate analysis.
Conclusion
These results suggest that TRT is not associated with a worse clinical outcome in men diagnosed with COVID-19.
Keywords: Androgens, COVID-19, Hypogonadism, SARS-CoV-2, Testosterone, Testosterone Replacement Therapy, Venous Thromboembolism
INTRODUCTION
The outbreak of coronavirus disease 2019 (COVID-19) demonstrates that men have less favorable disease outcomes than women.1 This suggests the possibility of a testosterone-mediated disease process for severe disease manifestations, which has led to the formulation of polar theories. The cytokine theory proposes that a low testosterone level leads to an increase in proinflammatory cytokines which may facilitate a cytokine storm in men with COVID-19.2 Conversely, the androgen-driven COVID-19 theory suggests that testosterone, via activation of a transmembrane protease (TMPRSS2), promotes infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).3 An increase in venous thromboembolism has also been associated with COVID-19, particularly in patients who are more severely affected.4 Testosterone replacement therapy (TRT) is associated with secondary polycythemia, but it is unclear whether this leads to an increase in thromboembolic events. However, some authors have suggested that men should be taken off TRT during this pandemic.5 Our objective was to determine the impact of TRT on the clinical outcomes of COVID-19 in men.
MATERIALS AND METHODS
After obtaining institutional review board approval, we performed a retrospective review identifying all men diagnosed with COVID-19 (ICD-10 code U07.1) who were on TRT from Henry Ford Health System during March to May 19, 2020. These men were propensity score matched in a ratio of 1:2 (using Greedy Nearest Neighbor method, caliper of 0.2) based on age, race, body mass index (BMI), and ZIP code (proxy for socioeconomic status) to men diagnosed with COVID-19 and not on TRT (controls). Standardized mean difference was ≤10% for all variables after matching. Comorbidity data including smoking status, hypertension, diabetes, chronic obstructive pulmonary disease, cardiovascular disease, chronic kidney disease, and immunosuppression status were collected. COVID-19–related endpoints were extracted including hospital admission, intensive care unit (ICU) admission, mechanical ventilator utilization, thromboembolic events, and death. Chi-square and Kruskal-Wallis tests examined differences in categorical and continuous variables, respectively. Logistic regression analysis tested the relationship between TRT status and the study endpoints. Covariates consisted of age, race, BMI, ZIP code, smoking status, and comorbidity (as a cumulative number).
RESULTS
A total of 3,697 men diagnosed with COVID-19 were identified of which 38 were on TRT. 6 men in the TRT group and 13 men in the control group had incomplete data and were excluded resulting in inclusion of 32 men in the TRT and 63 men in the control groups. Among men on TRT, 32 were diagnosed with hypogonadism (2 hypergonadotropic, 7 hypogonadotropic, and 23 mixed). 23 men received intramuscular testosterone cypionate injections while 9 were on transdermal testosterone gel. Descriptive characteristics are reported in Table 1 . Median age (IQR) was 53 years (46–65), and BMI (IQR) was 31 (27.4–36.3). Mean testosterone (IQR) level for those on TRT was 397 (212.5–454.75) ng/dl. Patients on TRT had higher rates of hypertension (65.6% vs 55.5%), cardiovascular disease (37.5% vs 30.1%), diabetes mellitus (40.6% vs 30.1%), and immunosuppression (25% vs 14.2%) and a lower rate of chronic obstructive pulmonary disease than controls (12.5% vs 25.4%), none of which were statistically significant (all P ≥ .1). When focusing on endpoints, patients on TRT had similar rates of hospitalization (62.5% vs 63.4%, P = .9), thromboembolic events (12.5% vs 12.7%, P = .7), and death (9.3% vs 12.7%, P = .7) as their counterparts not on TRT. Patients on TRT had lower rates of ICU admission (12.5% vs 25.4%, P = .1) and mechanical ventilator utilization (9.3% vs 19.0%, P = .2) than patients not on TRT, but none were statistically significant. TRT was not an independent predictor of any of the examined endpoints on multivariable analysis (Table 2).
Table 1.
Baseline characteristics and outcomes of 95 men diagnosed with COVID-19, stratified by testosterone replacement status
| Characteristics and outcomes | All patients (n = 95) | Testosterone replacement (n = 32) | Matched controls (n = 63) | P value |
|---|---|---|---|---|
| Age, years, median (IQR) | 53 (46–65) | 52 (45–66) | 54 (47–64) | .3 |
| Race, n (%) | ||||
| White | 70 (73.7) | 22 (68.8) | 48 (76.2) | |
| Black | 16 (16.8) | 6 (18.8) | 10 (15.9) | |
| Others | 9 (9.5) | 4 (12.5) | 5 (7.9) | .7 |
| BMI, median (IQR) | 31.5 (27.4–36.3) | 32.7 (27.9–38.0) | 31.2 (27.1–35.8) | .2 |
| Zip code, n (%) | ||||
| 480 | 16 (16.8) | 5 (15.6) | 11 (17.5) | |
| 481 | 39 (41.1) | 13 (40.6) | 26 (41.3) | |
| 482 | 10 (10.5) | 4 (12.5) | 6 (9.5) | |
| 483 | 16 (16.8) | 4 (12.5) | 12 (19.1) | |
| 492 | 14 (14.7) | 6 (18.8) | 8 (12.7) | .9 |
| Comorbidities before COVID-19, n (%) | .1 | |||
| COPD | 20 (21.1) | 4 (12.5) | 16 (25.4) | .5 |
| Cardiovascular disease | 31 (32.6) | 12 (37.5) | 19 (30.2) | .6 |
| Chronic kidney disease | 21 (22.1) | 6 (18.8) | 15 (23.8) | .3 |
| Diabetes | 32 (33.7) | 13 (40.6) | 19 (30.2) | .3 |
| Hypertension | 56 (59.0) | 21 (65.6) | 35 (55.6) | .2 |
| Immunosuppression | 17 (17.9) | 8 (25.0) | 9 (14.3) | |
| Smoking (current/former) | 44 (46.3) | 15 (46.9) | 29 (46.0) | .9 |
| Hospital admission for COVID-19, n (%) | 60 (63.2) | 20 (62.5) | 40 (63.5) | .9 |
| ICU admission for COVID-19, n (%) | 20 (21.1) | 4 (12.5) | 16 (25.4) | .1 |
| Thromboembolic event during COVID-19, n (%) | 12 (12.6) | 4 (12.5) | 8 (12.7) | .7 |
| Mechanical ventilation during COVID-19, n (%) | 15 (15.8) | 3 (9.4) | 12 (19.1) | .2 |
| Death due to COVID-19, n (%) | 11 (11.6) | 3 (9.4) | 8 (12.7) | .7 |
BMI = body mass index; COPD = chronic obstructive pulmonary disease; ICU = intensive care unit.
Table 2.
Multivariable logistic regression analysis testing the impact of testosterone replacement therapy on the clinical outcomes of men with new coronavirus infection 2019 (COVID-19)
| Endpoints | Odds ratio | 95% Confidence interval | Hosmer and Lemeshow goodness of fit |
|---|---|---|---|
| Hospital admission | 0.997 | 0.34–2.86 | 0.750 |
| Intensive care unit admission | 0.323 | 0.07–1.34 | 0.981 |
| Mechanical ventilator utilization | 0.465 | 0.10–2.08 | 0.650 |
| Thromboembolic event | 0.540 | 0.09–3.13 | 0.895 |
| Death | 1.713 | 0.13–21.24 | 0.611 |
All multivariable analyses were adjusted to age, race, body mass index, smoking status, comorbidity (as a cumulative number), and ZIP code. The control group was set as the reference category.
DISCUSSION
To our knowledge, this is the first study looking at outcomes of men on TRT who developed COVID-19. In our cohort, the thromboembolic and death rates were similar in both groups. Despite having a higher rate of baseline comorbidities, there were lower rates of ICU admission and mechanical ventilator utilization that were observed in the TRT group, although not statistically significant.
Androgens are needed for the SARS-CoV-2 to infect cells via activation of TMPRSS2 which serves to prime the spike protein needed for entry into cells.3 Based on this, clinical trials have begun with antiandrogens and TMPRSS2 inhibitors as prophylactic agents. There may also be a role for 5-α reductase inhibitors and luteinizing hormone–releasing hormone agonists/antagonists in this setting.6 In fact, it was found that even though patients diagnosed with cancer have an increased risk of contracting COVID-19, men on androgen deprivation therapy for prostate cancer had a lower risk of developing an infection.7
Once an infection occurs, testosterone may serve a protective role by decreasing the risk of a cytokine storm.2 A recent report observed lower levels of testosterone in men who were admitted to the ICU with SARS-CoV-2 infections.8 It is unknown whether these men had a low testosterone level at baseline or if they developed a low testosterone level in response to the infection. There is evidence to suggest that most men admitted to acute care units have a transient suppression of testosterone to a level below the normal range.9 A decreased testosterone level is associated with an increase in proinflammatory markers such as IL-1β, IL-6, and TNF-α.10 Testosterone may facilitate cell infection with the SARS-CoV-2 but also be protective of worse clinical outcomes during active infections. A study measuring testosterone levels of men at baseline and at various times during COVID-19 may help further delineate this relationship.
Androgens appear to play an important role in COVID-19, but the overall clinical picture is a much more complex interplay between exposure risks, age, comorbidities, genetic predisposition, and socioeconomic status. A combination of these factors may be responsible for the differences in disease severity between men and women. Limitations of this study include a small sample size, which limits the statistical power of the study. Other limitations are unknown testosterone levels in men of the control cohort and the retrospective nature of this study with the potential for residual bias caused by unobserved confounders, even after propensity score matching. In conclusion, our study failed to demonstrate a statistically significant difference in COVID-19 outcomes among men treated with TRT and those not on TRT. Future studies are needed to help further guide clinicians on the optimal management of hypogonadism with TRT in the era of COVID-19.
STATEMENT OF AUTHORSHIP
Amarnath Rambhatla: Writing - Original Draft, Formal Analysis, Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition, Writing - Original Draft, Formal Analysis, Project Administration; Chandler J. Bronkema: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Nicholas Corsi: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Jacob Keeley: Writing - Original Draft, Formal Analysis, Writing - Original Draft, Formal Analysis, Project Administration; Akshay Sood: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Ziad Affas: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Ali A. Dabaja: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Craig G. Rogers: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Stephen A. Liroff: Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition; Firas Abdollah: Writing - Original Draft, Formal Analysis, Conceptualization, Methodology, Investigation, Resources, Writing - Review & Editing, Funding Acquisition, Writing - Original Draft, Formal Analysis, Project Administration.
Funding
None.
Contributor Information
Amarnath Rambhatla, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
Chandler J. Bronkema, School of Medicine, Wayne State University, Detroit, MI, USA; Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
Nicholas Corsi, School of Medicine, Wayne State University, Detroit, MI, USA; Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
Jacob Keeley, Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
Akshay Sood, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA; Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
Ziad Affas, Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
Ali A. Dabaja, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
Craig G. Rogers, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
Stephen A. Liroff, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
Firas Abdollah, Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA; Center for Outcomes Research Analytics and Evaluation, Vattikuti Urology Institute, Detroit, MI, USA.
REFERENCES
- 1. Onder G., Rezza G., Brusaferro S.. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020;323: 1775–1776. [DOI] [PubMed] [Google Scholar]
- 2. Pozzilli P., Lenzi A.. Commentary: testosterone, a key hormone in the context of COVID-19 pandemic. Metabolism 2020;108: 154252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Wambier C.G., Goren A.. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol 2020;83: 308–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Middeldorp S., Coppens M., van Haaps T.F.et al. . Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020;18: 1995–2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. La Vignera S., Cannarella R., Condorelli R.A.et al. . Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D. Int J Mol Sci 2020;21: 2948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Wambier C.G., Goren A., Vaño-Galván S.et al. . Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev Res 2020. 10.1002/ddr.21688 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Montopoli M., Zumerle S., Vettor R.et al. . Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n=4532). Ann Oncol 2020;31: 1040–1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Rastrelli G., Di Stasi V., Inglese F.et al. . Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2020. 10.1111/andr.12821 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Spratt D.I., Bigos S.T., Beitins I.et al. . Both hyper- and hypogonadotropic hypogonadism occur transiently in acute illness: bio- and immunoactive gonadotropins. J Clin Endocrinol Metab 1992;75: 1562–1570. [DOI] [PubMed] [Google Scholar]
- 10. Mohamad N.V., Wong S.K., Wan Hasan W.N.et al. . The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male 2019;22: 129–140. [DOI] [PubMed] [Google Scholar]