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What does the evidence say on the effect of total serum testosterone and its relationship with other laboratory parameters on the prognosis of Corona Virus Disease 2019 (COVID-19) in infected male patients?

Comment by InpharmD Researcher

Serum testosterone levels may decrease due to COVID-19 in severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infected male patients, which could increase the risk for intensive care unit (ICU) admission and mortality.

1. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [10/12/20] 2. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, Edwards KM, Gandhi R, Muller WJ, O'Horo JC, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Clin Infect Dis. 2020 Apr 27:ciaa478. doi: 10.1093/cid/ciaa478. Epub ahead of print. PMID: 32338708; PMCID: PMC7197612. 3. Guidelines - American Urological Association. https://www.auanet.org/guidelines. Accessed October 12, 2020. 4. Giagulli VA, Guastamacchia E, Magrone T, et al. Worse progression of COVID-19 in men: Is testosterone a key factor? [published online ahead of print, 2020 Jun 11]. Andrology. 2020;10.1111/andr.12836. doi:10.1111/andr.12836 5. Maleki Dana P, Sadoughi F, Hallajzadeh J, et al. An Insight into the Sex Differences in COVID-19 Patients: What are the Possible Causes?. Prehosp Disaster Med. 2020;35(4):438-441. doi:10.1017/S1049023X20000837 6. Al-Lami RA, Urban RJ, Volpi E, Algburi AMA, Baillargeon J. Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19). Mayo Clin Proc. 2020;95(8):1710-1714. doi:10.1016/j.mayocp.2020.05.013 7. Sansone A, Mollaioli D, Ciocca G, et al. Addressing male sexual and reproductive health in the wake of COVID-19 outbreak [published online ahead of print, 2020 Jul 13]. J Endocrinol Invest. 2020;1-9. doi:10.1007/s40618-020-01350-1 8. Pradhan A, Olsson PE. Sex differences in severity and mortality from COVID-19: are males more vulnerable?. Biol Sex Differ. 2020;11:53. Published 2020 Sep 18. doi:10.1186/s13293-020-00330-7 9. Chanana N, Palmo T, Sharma K, Kumar R, Graham BB, Pasha Q. Sex-derived attributes contributing to SARS-CoV-2 mortality. Am J Physiol Endocrinol Metab. 2020;319(3):E562-E567. doi:10.1152/ajpendo.00295.2020



Background

There is no mention of serum testosterone levels for males infected by COVID-19 in the National Institute of Health COVID-19 Treatment Guidelines. [1]

There is no mention of serum testosterone levels for males infected by COVID-19 in the Infectious Diseases Society of America COVID-19 Treatment Guidelines. [2]

The American Urological Association has published articles relating to COVID-19. However, there is no mention of COVID-19 and serum testosterone in their clinical guidelines. [3]

A review article assessing whether testosterone could worsen COVID-19 outcomes in men concluded that testosterone, in comparison to estrogen, may predispose men to widespread COVID-19 infection. Low serum levels of testosterone may predispose men, especially elderly men, to poor prognosis or death. [4]

A review article assessing gender differences in COVID-19 concluded that different levels of angiotensin-converting enzyme 2 (ACE2) in men and women, the effects of testosterone on ACE2 levels, and the fact that the ACE2 gene is located on the X-chromosome could contribute to men having a higher risk of developing severe COVID-19. [5]

A review article assessing the role of sex hormones in COVID-19 concluded that testosterone might reduce the need for assisted ventilation through its anticatabolic effect on respiratory muscles and could be considered in developing treatment strategies for patients with COVID-19. [6]

A review article assessing male reproductive health during COVID-19 concluded that testicular function in COVID-19 patients may need to be studied due to potential negative association on testosterone levels and overall reproductive health. Treatment with phosphodiesterase-5 (PDE5) inhibitors might be beneficial for both COVID-19 and erectile dysfunction in these patients. [7]

A review article assessing sex differences in severity and mortality in COVID-19 found that coronavirus genetic material was detected in the semen samples of infected males. Analysis of RNA sequencing data showed that both angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) were highly expressed in the testis compared to the ovary, supporting that coronavirus may enter the human testis. The researchers concluded that there is male-biased severity and mortality in different countries. However, sex-biased pathogenesis is not understood properly and could be multifactorial. [8]

A review article assessing sex-derived attributes contributing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mortality found that a greater COVID-19 fatality rate in men could be a consequence of several biological differences between the sexes, and may be hypothesized as a result of suppressed immune responses due to testosterone. [9]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What does the evidence say on the effect of total serum testosterone and its relationship with other laboratory parameters on the prognosis of Corona Virus Disease 2019 (COVID-19) in infected male patients?

Please see Table 1 for your response.


Study Name

Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study

 

Design

Prospective cohort study

N= 221

Objective

To investigate effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of COVID-19 in SARS-CoV-2 infected male patients

Methods

Inclusion criteria:adult males with laboratory confirmed SARS-CoV-2 who had been hospitalized due to COVID-19.

Patients were divided into three groups: asymptomatic patients, patients hospitalized in the internal medicine unit (IMU), and patients hospitalized in the intensive care unit (ICU).

All data were prospectively collected and included a detailed clinical history, complete physical examination, laboratory and radiological imaging studies.

The criteria for discharge were absence of fever for at least two days, improvement in both lungs on the chest computed tomography (CT) scan, clinical remission of respiratory symptoms, and two throat-swab samples negative for SARS-CoV-2 RNA, obtained at least 24 hours apart.

Venous serum samples were obtained to determine serum follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol (E2) and total testosterone levels in every patient.

Hypogonadism was considered as the presence of serum total testosterone level of < 300 ng/dL.

In the asymptomatic patients, sexual functions were assessed using the nationally validated international index of erectile function-erectile function domain (IIEF-EF) questionnaire.

 

Study Groups/Patients

Asymptomatic patients: (n= 46)

 

Symptomatic patients who were hospitalized in the IMU: (n= 129)

 

Patients who were hospitalized in ICU: (n= 46)

Outcome Measures

Outcomes were not specified by the researchers.

 

Results

 

Mean serum gonadal levels of patients according to the groups:

 

P-value

Mean FSH (mIU/mL):

Asymptomatic vs IMU: 0.222

 

Asymptomatic vs ICU: 0.02

 

IMU vs ICU: 0.176

Asymptomatic

5.26

IMU

6.67

ICU

8.41

Mean LH (mIU/mL):

Asymptomatic vs IMU: 0.758

 

Asymptomatic vs ICU: 0.699

 

IMU vs ICU: 0.935

Asymptomatic

5.31

IMU

5.73

ICU

5.97

Mean Total Testosterone (ng/dL):

Asymptomatic vs IMU: 0.563

 

Asymptomatic vs ICU: 0.006

 

IMU vs ICU: 0.017

Asymptomatic

346

IMU

318

ICU

241

Mean Prolactin (pg/mL):

Asymptomatic vs IMU: 0.625

 

Asymptomatic vs ICU: 0.346

 

IMU vs ICU: 0.662

Asymptomatic

8.71

IMU

9.81

ICU

11.05

Mean Estradiol (pg/mL):

Asymptomatic vs IMU: 0.982

 

Asymptomatic vs ICU: 1.000

 

IMU vs ICU: 0.991

Asymptomatic

26.18

IMU

25.71

ICU

26.1

 

Comparison of mean total testosterone levels in the presence of various findings and parameters in the COVID-19 patients:

 

 

Presence

Mean (ng/dL)

p-value

Symptoms

 

+

344.78

0.058

 

298.18

Fever

 

+

290.36

0.179

 

321.10

Respiratory findings

 

+

306.46

0.912

 

308.93

Chest CT findings

 

+

294.69

0.173

 

325.05

CCI score

 

>2

257.45

0.001

 

0 and 1

336.50

ICU

 

+

239.94

0.001

 

326.73

Intubation

 

+

195.13

0.048

 

312.11

Death

 

+

158.45

0.001

 

315.70

D-dimer (mg/l)

 

>1

224.33

0.009

 

<1

343.10

 

ICU patients and testosterone levels:

Patients (n= 46)

Total testosterone (ng/dL)

76.0% (35/46)

< 300

45.6% (21/46)

<200

 

Death and testosterone levels:

Total death: 4.97% (11/221)

Total testosterone (ng/dL)

90.9% (10/11)

< 300

72.7% (8/11)

<200

 

 

Study Author Conclusions

COVID-19 might deteriorate serum testosterone level in SARS-CoV-2 infected male patients. Low serum total testosterone level at baseline has a significant increased risk for the ICU and mortality in patients with COVID-19.

InpharmD Researcher Critique

COVID-19 might deteriorate serum testosterone level in SARS-CoV-2 infected male patients. Testosterone levels should be compared to a control group in further studies for more conclusive results. 

 

 

References:

Çayan S, Uğuz M, Saylam B, Akbay E. Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study. Aging Male. 2020 Sep 3:1-11. doi: 10.1080/13685538.2020.1807930. Epub ahead of print. PMID: 32883151.