REVIEW Effects of Androgen Deprivation Therapy on COVID-19 in Patients with Prostate Cancer: A Systematic Review and Meta-Analysis Amirali Karimi1, Ali Nowroozi1, Sanam Alilou1, Erfan Amini1,* Purpose: Transmembrane serine protease 2 (TMPRSS2) facilitates SARS-CoV-2 cellular entry. Androgens reg- ulate this protein and may increase the risk of COVID-19. Therefore, androgen deprivation therapy (ADT) may protect patients with prostate cancer from SARS-CoV-2 infection or decrease the severity of the disease. There- fore, we conducted a meta-analysis to study the effect of androgen deprivation therapy (ADT) on COVID-19 in patients with prostate cancer. Methods: We systematically searched PubMed, Embase, Scopus, and Cochrane databases. All records underwent a two-step screening process to identify the eligible studies. The registered PROSPERO number of this study was CRD42021228398. We evaluated the effect of ADT on the risk of infection, hospitalization, ICU admission, and mortality. Results: Six studies met inclusion criteria and were evaluated in this study. We performed meta-analysis on four eligible studies. The overall incidence of COVID-19 was 2.65% among patients with prostate cancer receiving ADT. COVID-19 mortality rate was about 22.7% in ADT (+) patients. ADT did not decrease the risk of any of the major outcomes; infection risk (OR= 0.63, 95% CI= 0.27- 1.48, P = 0.29), hospitalization rate (OR= 0.51, 95% CI= 0.10- 2.53, P = 0.41), ICU admission (OR= 1.11, 95% CI= 0.43- 2.90, P = 0.82), and mortality risk (OR= 1.21, 95% CI= 0.34- 4.32, P = 0.77). Conclusion: We did not observe a protective effect on the risk of infection, hospitalization, ICU admission, and mortality in patients receiving ADT; therefore, it should not be considered as a prophylactic or treatment for COVID-19. On the other hand, ADT did not increase the mortality and morbidity of COVID-19 and should be considered a safe treatment for patients with prostate cancer during the pandemic. Further studies are necessary to confirm our findings. Keywords: Androgens; COVID-19; Prostatic neoplasms; SARS-CoV-2 INTRODUCTION As of January 27th, Coronavirus disease 2019 (COVID-19) has imposed a tremendous human toll of 99,638,507 deaths and 2,141,468 cases since its inaugural.(1,2) This devastating burden resulted in an ex- plosion of ideas and hypotheses to cure or prevent the disease.(3) Androgen deprivation therapy (ADT) turned out to be one of these hypothetical solutions.(4-7) Transmembrane serine protease 2 (TMPRSS2) facili- tates severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) cellular entry and serves as the princi- pal protease in this process.(8-12) TMPRSS2 initiates vi- ral fusion and host cell-receptor binding by cleaving the SARS-CoV-2 spike (S) protein and angiotensin-con- verting enzyme- 2 (ACE-2).(11-15) Many patients with prostate cancer also suffer from TMPRSS2 fusion as a common genetic abnormality in this disease.(6) High- er testosterone levels upregulate TMPRSS2 and can theoretically increase the risk of viral transmission.(4,5) Earlier studies raised the idea that the increased risk of infection and mortality in men might correlate with this molecular phenomenon.(16-19) Therefore, ADT raised 1Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran. *Correspondence: Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran. amini.erfan@gmail.com Received February 2021 & Accepted July 2021 hopes as a novel approach to fight COVID-19.(4-6) ADT is a standard treatment for many patients with high-risk and advanced prostate cancer.(20-24) This ap- proach constitutes various treatments with similar ide- as, ranging from bilateral orchiectomy, to novel medi- cations such as LHRH (luteinizing hormone-releasing hormone) antagonists and CYP17 inhibitors.(6,25-27) To examine the aforementioned hypothesis, several arti- cles assessed the outcomes of COVID-19 in patients with prostate cancer who received ADT compared with those who did not. In this meta-analysis, we aim to ex- amine the effect of ADT prescribed for prostate cancer patients on their risk of COVID-19 infection and the subsequent outcomes. MATERIALS AND METHODS Design This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines. We systematically searched PubMed, Scopus, Embase, and Cochrane libraries on December 26th. The retrieved records followed a two-step screen- ing process. First, the articles were screened based on Urology Journal/Vol 18 No. 6/ November-December 2021/ pp. 577-584. [DOI: 10.22037/uj.v18i.6691] the overall coherence of their title and abstract to our in- clusion criteria. The qualified articles were assessed by their full-texts, and the eligible articles were included for the qualitative and quantitative synthesis. This me- ta-analysis was registered in PROSPERO (International Prospective Register of Systematic Reviews) with the ID CRD42021228398. PICO 1. Population: Patients with prostate cancer 2. Intervention: Receiving ADT 3. Comparison: Not receiving ADT 4. Outcomes: 1) COVID-19 infection risk; 2) COV- ID-19 severity risk, including: 1. Hospitalization risk, 2. ICU admission, and 3. Mortality risk Search strategy We searched the keywords for ADT and COVID-19 us- ing the search strategy [C]. [Androgen deprivation therapy] (Title/Abstract) OR [Androgen deprivation therapies] (Title/Abstract) OR [Androgen targeted therapy] (Title/Abstract) OR [An- drogen targeted therapies] (Title/Abstract) OR [Andro- gen deprivation] (Title/Abstract) OR [Androgen] (Title/ Abstract) [COVID-19] (Title/Abstract) OR [SARS-CoV-2] (Ti- tle/Abstract) OR [SARS-CoV2] (Title/Abstract) OR [Novel Coronavirus] (Title/Abstract) OR [2019-nCoV] (Title/Abstract) [A] AND [B] Inclusion/Exclusion criteria Original clinical articles, from the start of the pandemic until December 26th, demonstrating the effect of ADT on the COVID-19 were included. No language restric- tion was considered in this study. Exclusion criteria were the following: 1) Review, guidelines, editorials, or other articles not possessing original data 2) Case reports 3) Incomplete projects and clinical trials 4) Animal and laboratory studies without clinical data Data acquisition and analysis We completely read the full-texts and extracted the data into an excel sheet. We classified the major extracted outcomes into four categories and estimated their risks; ID First author Country Type of study Newcastle-Ottawa scale (NOS) risk of bias assessment Selection Comparability Exposure Total score (out of 9) 1 Klein, E. A. (29) USA Prospective cohort **** ** *** 9 2 Koskinen, M. (30) Finland Retrospective cohort **** ** ** 8 3 Montopoli, M. (31) Italy Retrospective cohort **** - ** 6 4 Patel, V. G. (32) USA Retrospective cohort **** ** ** 8 5 Caffo, O. (33) Italy Retrospective cohort *** - ** 5 6 Caffo, O. (34) Italy Retrospective cohort *** - *** 6 Table1. Characteristics and NOS risk of bias assessment scale of the studies Androgen deprivation therapy and COVID-19- Karimi et al. Review 578 Figure 1. Prisma flow diagram of the study selection process COVID-19 infection, hospitalization, ICU (Intensive care unit) admission, and mortality. Besides the above- mentioned four major outcomes, we also extracted country, population, mean age, and comorbidities into the same excel sheet. Higgins I2 test was utilized to examine heterogeneity among the studies. I2 levels of above 40% represented heterogeneity among data of the subgroups and war- ranted a random effects analysis.(28) We used fixed ef- fect analysis to evaluate the groups that were classified as low in the heterogeneity test. We used Egger’s test and funnel plot to assess the po- tential publication bias for each major outcome in this study. Meta-analyses were conducted using the latest version of the Cochrane review manager released in Septem- ber 2020 (Revman 5.4.1). Publication bias and pooled analyses were performed using Stata version 16. The visualizations for each part were illustrated using their corresponding software. We used Odds ratio (OR) to assess the outcomes and P= 0.05 as the threshold of sig- nificance. Risk of bias assessment Newcastle-Ottawa Scale (NOS) risk assessment tool was applied to calculate the risk of bias of the included studies. This tool provides a maximum score of nine for each study in three categories of selection, comparabil- ity, and exposure. RESULTS We identified 50 non-duplicate records by searching PubMed, Embase, Scopus, and Cochrane databases. Following the title/abstract and full-text screening, six related original articles were included for conducting this systematic review. Four studies were eligible for meta-analysis as they comprised both ADT (+) and ADT (-) groups (Figure 1).(29-32) The remaining two studies comprised only ADT (+) patients, and did not have ADT (-) controls. Therefore, they were exclud- ID First author Total no. Age Dosage and Comorbidities Total no. of Assessed (b) (mean ± SD) duration of ADT infected patients variables 1 Klein, E. A. (29) Total: 1779 Total: 74.1 ± 10.3 N/A 1. Smoking history: Total: 102 COVID-19 infection ADT (+): 304 ADT (+): 75.7 ± 10.9 ADT (+): 68.1% ADT (+): 17 Hospitalization ADT (-): 1475 ADT (-): 73.8 ± 10.2 ADT (-): 59.3% ADT (-): 85 ICU admission (P < .009) (P < .005) Death 2. Immune-suppressive disease: ADT (+): 34.2% ADT (-): 27.5% (P = .02) 3. Steroid use: ADT (+): 43.8% ADT (-): 23.3% (P < .001) 4. Asthma: ADT (+): 9.2% ADT (-): 14.2% (P = .02) 5. No significant difference in HTN, CAD, HF, and diabetes mellitus. 2 Koskinen, M. (30) Total: 352 Total: 77.2 ± 9.0 N/A No significant differences Total: 17 COVID-19 infection ADT (+): 134 ADT (+): 78.4 ± 8.1 in: HTN, CAD, COPD, ADT (+): 6 ICU admission ADT (-): 218 ADT (-): 76.5 ± 9.4 diabetes mellitus, ADT (-): 11 arrhythmia, smoking history 3 Montopoli, M. (31) Total: 42434 N/A N/A N/A Total: 118 COVID-19 infection ADT (+): 5273 ADT (+): 4 Disease severity ADT (-): 37161 ADT (-): 114 Hospitalization ICU admission Death 4 Patel, V. G. (32) N/A N/A 1. GnRH analog/agonis 1. Metastatic disease: Total: 58 Hospitalization within 3 months and/or ADT (+): 64% ADT (+): 22 O 2 supplementation 2. documented ADT (-): 0% ADT (-): 36 Intubation Death testosterone concentrations (P < .001) ≤ 50 ng/dL within 6 months 2. Underlying pulmonary of COVID-19 diagnosis disease: ADT (+): 27% ADT (-): 6% (P = .02) 3. No significant difference in other comorbidities (not mentioned specifically) 5 Caffo, O. (33) 1949 Median age: 74.5 N/A N/A 36 COVID-19 infection Hospitalization Death 6 Caffo, O. (34) 1433 75.4 ± 9.6 Median duration: 50 N/A 34 COVID-19 infection months (IQR: 19-66) Hospitalization ICU admission O 2 supplementation Intubation Death Table 2. Characteristics of prostate cancer patients with SARS-CoV-2 infection in the included studies a Abbreviations: SD: Standard deviation, ADT: Androgen deprivation therapy, ICU: Intensive care unit, HTN: Hypertension, CAD: Coronary artery disease, HF: Heart failure, N/A: data “Not available”, COPD: Chronic obstructive pulmonary disease, GnRH: Gonado- tropin releasing hormone, IQR: Interquartile range, b Total number applies to the prostate cancer patients reported in each study. For the last two studies, all of the patients received ADT. Androgen deprivation therapy and COVID-19- Karimi et al. Vol 18 No 6 November-December 2021 579 ed from meta-analysis between ADT (+) and ADT (-) groups.(33,34) In addition, these studies were performed on a similar population. Therefore, if both studies re- ported a variable in ADT (+) patients, we only consid- ered the larger study.(33) Table 1 describes the risk of bias for the included stud- ies. Five studies (three of those included in the com- parative analysis) belonged to Italy and the USA, both highly stormed by the COVID-19 pandemic. Most stud- ies scored well according to the NOS (Mean ± SD = 7 ± 1.1). Baseline characteristics Mean patient age was comparable between ADT (+) and ADT (–) groups in one study(30) whereas another study reported higher mean age among ADT (+) pa- tients (mean age: 75.7 vs. 73.8, P < .009) (Table 2).(29) Three studies reported comorbidities.(29,30,32) Although one study reported similar frequency of various comor- bidities in ADT (+) and (-) groups,(30) two other studies Review 580 Figure 2. Pooled analysis of COVID-19 rate in patients receiving ADT Figure 3. Meta-analysis of the subgroups with high heterogeneity Androgen deprivation therapy and COVID-19- Karimi et al. reported higher comorbidity rates among ADT (+) pa- tients.(29,32) In Patel et al. study, patients using ADT en- dured higher rates of metastatic (64% vs. 0%, P < .001) and underlying pulmonary diseases (27% vs. 6%, P = .02).(32) Patients receiving ADT in Klein et al.'s study were more likely to have smoking history (68.1% vs. 59.3% P < .005), immune-suppressive disease (34.2% vs. 27.5%, P = .02), and steroid use (43.8% vs. 23.3%, P < .001), and less likely to have a history of asthma (9.2% vs. 14.2%, P = .02).(29) COVID-19 infection risk Pooled analysis showed that SARS-CoV-2 infection rate among patients receiving ADT was 2.65% (Fig- ure 2).(29-31,33) ADT was not associated with a decreased COVID-19 infection risk (95% CI: 0.27-1.48, OR = 0.63, P = .29) (Figure 3). Components of disease severity Hospitalization risk: Hospital admission was recorded in 62.1% of the infect- ed patients in the ADT (+) group (Figure 4).(29-33) ADT use did not affect the risk of hospitalization (95% CI: 0.10-2.53, OR = 0.51, P = .41) (Figure 3). ICU admission risk: One study combined data of ICU admission with mor- tality.(30) We assumed all these patients as requiring ICU admission; however, we did not utilize these data to assess mortality risk. Among ADT (+) patients who were infected with SARS-CoV-2, 18.3% required ICU admission (Figure 5)(29-32,34) and ADT did not decrease the likelihood of ICU admission (95% CI: 0.43-2.90, OR = 1.11, P = .82) (Figure 6). Mortality risk: We included five appropriate studies to estimate the mortality rate and association between ADT use and risk of mortality.(29-33) The mortality rate was about 22.7% (Figure 7) and was not associated with ADT use (95% CI: 0.34-4.32, OR = 1.21, P = .77) (Figure 3). Publication bias We performed Egger’s test and funnel plot to test pub- lication bias of all the four major outcomes. None of the variables had significant publication bias: COV- ID-19 infection (P for Egger’s test = .50, funnel plot as Supplementary Figure 1), hospitalization (P = .59, Supplementary Figure 2), ICU admission (P = .98, Supplementary Figure 3), mortality (P = 0.58, Sup- plementary Figure 4). DISCUSSION We found that ADT use could not reduce COVID-19 infection, hospitalization, ICU admission, or mortality risks. On the other hand, they also did not face elevated risks of complications related to ADT. Prostate cancer patients who are receiving ADT usually suffer from more comorbidities, advanced disease, and higher risk of mortality.(21,35) Three studies that were in- cluded in the comparative analysis reported the patients’ age and underlying disease status. Overall, patients in the ADT (+) group seemed to have more comorbidities than ADT (-) patients. This may mask the potential pro- tective effects of ADT on COVID-19.(29,30,32) SARS-CoV-2 infection rate among ADT (+) patients was 2.65%. This rate might be associated with both un- derestimation and overestimation. Most studies were from Italy and the USA, two of the world's worst-hit countries with the potential to overestimate the risk of infection. On the other hand, missing many patients with milder symptoms who did not seek care might un- derestimate the true rate of COVID-19 in the ADT (+) Figure 4. Pooled analysis of hospitalization rate in COVID-19 patients receiving ADT Androgen deprivation therapy and COVID-19- Karimi et al. Vol 18 No 6 November-December 2021 581 patients. The main limitation of this meta-analysis is the limit- ed number of studies and patients due to the novelty of the subject. Results were not adjusted for confounding factors including comorbidities and disease stage. The dosage and duration of ADT was also not mentioned in most of the studies. Our study is the first meta-analysis on this subject, providing valuable information on ADT and the risk of COVID-19 and included studies were relatively homogeneous in terms of methodology. More investigations are needed to better identify the role of ADT in COVID-19. CONCLUSIONS ADT showed a modest protective effect on COVID-19 and only one of the five parameters were associated with ADT use. However, ADT did not increase the morbidi- ty and mortality related to COVID-19. Therefore, ADT should be considered safe and physicians should not hesitate to administer this treatment to the candidates during the pandemic. Further studies with larger sample size are necessary to obtain more definitive results. CONFLICTS OF INTEREST The authors declare that they have no conflicts of in- terest. Review 582 Figure 5. Pooled analysis of ICU admission rate in COVID-19 patients receiving ADT Figure 6. 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