key: cord-1005746-ceytvuxo
authors: Camici, Marta; Zuppi, Paolo; Lorenzini, Patrizia; Scarnecchia, Liliana; Pinnetti, Carmela; Cicalini, Stefania; Nicastri, Emanuele; Petrosillo, Nicola; Palmieri, Fabrizio; D’Offizi, Gianpiero; Marchioni, Luisa; Gagliardini, Roberta; Baldelli, Roberto; Schininà, Vincenzo; Pianura, Elisa; Di Stefano, Federica; Curcio, Stefano; Ciavarella, Lucia; Ippolito, Giuseppe; Girardi, Enrico; Vaia, Francesco; Antinori, Andrea; Abbonizio, Maria Alessandra; Abdeddaim, Amina; Agostini, Elisabetta; Agrati, Chiara; Albarello, Fabrizio; Amadei, Gioia; Amendola, Alessandra; Antonica, Maria Assunta; Antonini, Mario; Bartoli, Tommaso Ascoli; Baldini, Francesco; Barbaro, Raffaella; Bartolini, Barbara; Bellagamba, Rita; Benigni, Martina; Bevilacqua, Nazario; Biava, Gianluigi; Bibas, Michele; Bordi, Licia; Bordoni, Veronica; Boumis, Evangelo; Branca, Marta; Buonomo, Rosanna; Busso, Donatella; Campioni, Paolo; Canichella, Flaminia; Capobianchi, Maria Rosaria; Capone, Alessandro; Caporale, Cinzia; Caraffa, Emanuela; Caravella, Ilaria; Carletti, Fabrizio; Castilletti, Concetta; Cataldo, Adriana; Cerilli, Stefano; Cerva, Carlotta; Chiappini, Roberta; Chinello, Pierangelo; Cianfarani, Maria Assunta; Ciaralli, Carmine; Cimaglia, Claudia; Cinicola, Nicola; Ciotti, Veronica; Colavita, Francesca; Corpolongo, Angela; Cristofaro, Massimo; Curiale, Salvatore; D’Abramo, Alessandra; Dantimi, Cristina; Angelis, Alessia De; Angelis, Giada De; Palo, Maria Grazia De; Zottis, Federico De; Bari, Virginia Di; Lorenzo, Rachele Di; Stefano, Federica Di; Donno, Davide; Evangelista, Francesca; Faraglia, Francesca; Farina, Anna; Ferraro, Federica; Fiorentini, Lorena; Frustaci, Andrea; Fusetti, Matteo; Galati, Vincenzo; Gallì, Paola; Garotto, Gabriele; Gaviano, Ilaria; Tekle, Saba Gebremeskel; Giancola, Maria Letizia; Giansante, Filippo; Giombini, Emanuela; Granata, Guido; Greci, Maria Cristina; Grilli, Elisabetta; Grisetti, Susanna; Gualano, Gina; Iacomi, Fabio; Iaconi, Marta; Iannicelli, Giuseppina; Inversi, Carlo; Lalle, Eleonora; Lamanna, Maria Elena; Lanini, Simone; Lapa, Daniele; Lepore, Luciana; Libertone, Raffaella; Lionetti, Raffaella; Liuzzi, Giuseppina; Loiacono, Laura; Lucia, Andrea; Lufrani, Franco; Macchione, Manuela; Maffongelli, Gaetano; Marani, Alessandra; Mariano, Andrea; Marini, Maria Cristina; Maritti, Micaela; Mastrobattista, Annelisa; Mastrorosa, Ilaria; Matusali, Giulia; Mazzotta, Valentina; Mencarini, Paola; Meschi, Silvia; Messina, Francesco; Micarelli, Sibiana; Mogavero, Giulia; Mondi, Annalisa; Montalbano, Marzia; Montaldo, Chiara; Mosti, Silvia; Murachelli, Silvia; Musso, Maria; Nardi, Michela; Navarra, Assunta; Nocioni, Martina; Noto, Pasquale; Noto, Roberto; Oliva, Alessandra; Onnis, Ilaria; Ottou, Sandrine; Palazzolo, Claudia; Pallini, Emanuele; Palombi, Giulio; Pareo, Carlo; Passeri, Virgilio; Pelliccioni, Federico; Penna, Giovanna; Petrecchia, Antonella; Petrone, Ada; Pisciotta, Maria; Piselli, Pierluca; Pittalis, Silvia; Pontarelli, Agostina; Proietti, Costanza; Puro, Vincenzo; Ramazzini, Paolo Migliorisi; Rianda, Alessia; Rinonapoli, Gabriele; Rosati, Silvia; Rubino, Dorotea; Rueca, Martina; Ruggeri, Alberto; Sacchi, Alessandra; Sampaolesi, Alessandro; Sanasi, Francesco; Santagata, Carmen; Scarabello, Alessandra; Scarcia, Silvana; Scognamiglio, Paola; Scorzolini, Laura; Stazi, Giulia; Strano, Giacomo; Taglietti, Fabrizio; Taibi, Chiara; Taloni, Giorgia; Nardi, Tetaj; Tonnarini, Roberto; Topino, Simone; Tozzi, Martina; Vairo, Francesco; Valli, Maria Beatrice; Vergori, Alessandra; Vincenzi, Laura; Visco-Comandini, Ubaldo; Vita, Serena; Vittozzi, Pietro; Zaccarelli, Mauro; Zanetti, Antonella; Zito, Sara
title: The role of testosterone in SARS-CoV-2 infection: a key pathogenic factor and a biomarker for severe pneumonia
date: 2021-05-20
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.05.042
sha: 04895283adf415ccd29a79c5caf89838430c33ba
doc_id: 1005746
cord_uid: ceytvuxo

Objectives The aim of the study was to investigate the association between sex hormones and SARS-CoV-2 infection severity. Furthermore, the associations between sex hormones and systemic inflammation markers, viral shedding and length of patients’ hospitalization were studied. Design and Methods We conducted a case-control study, including 48 SARS-CoV-2 male patients, admitted to an Italian reference Hospital. The cases were composed by 24 patients with PaO2/FiO2 < 250 mmHg and needed ventilatory support (severe COVID-19). The controls were selected in a 1:1 ratio, matching by ages, among patients who may receive a low-flow oxygen supplementation (mild COVID-19). For each group, sex hormones at hospitalization were evaluated. Results Severe COVID-19 patients had a significantly lower Testosterone levels than mild COVID-19 patients. The median total testosterone (TT) was 1.4 ng/mL in cases and 3.5 ng/mL in controls (p = 0.005); the median bioavailable testosterone was 0.49 and 1.21 (p = 0.008); the median calculated Free Testosterone (cFT) was 0.029 ng/mL and 0.058 ng/mL (p = 0.015), respectively. Either low TT, low cFT and low BioT were correlated to the hyperinflammatory syndrome (p = 0.018, p = 0.048 and p = 0.020) and associated to a longer hospitalization (p = 0.052, p = 0.041 and p = 0.023), respectively. No association was found between hormones and duration of viral shedding nor mortality rate. Conclusions According to our data, lower level of Testosterone is a marker of clinical severity for COVID-19.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a huge variability of clinical manifestations. Many pathogenetic pathways and virulence mechanisms are still unknown. Nevertheless, it is known that host's immune system plays a key role in the J o u r n a l P r e -p r o o f damage setting-up [2] . Notably, age, comorbidities (e.g. diabetes mellitus, obesity), smoking habits and male sex [17, 27] are the fundamental independent mortality risk factor for CoronaVirus [28] . A study conducted by Jian-Min Jin et al. [10] showed that, as for SARS infection, the number of men who died from COVID-19 is 2.4 times that of women (p= 0.016), without a different prevalence by gender. The COVID-19 Sex-Disaggregated Data Tracker, reported COVID-19 fatality rate is higher in men in 68 countries as compared with women, indeed.

[30]. For such discrepancy behavioural and genetics features have been called into question.

TMPRSS2 receptor is a serin-protease expressed over the surface of type II pneumocytes, that largely contribute to the virus penetration into the host cells [9] and which is required for SARS-CoV-2 infectivity [8, 20] . Interestingly, the androgen receptor is the main activator of transcription of the TMPRSS2 gene in humans [12, 22] . Moreover, a study conducted by Seeland et al. showed that oestrogens are protective for severe COVID-19 by under-regulating the expression of Angiotensin-converting enzyme 2 (ACE-2) receptor [18] . Interestingly, has been shown that SARS-CoV-2 infected men had lower testosterone serum levels en respect to general population [11] .While, a recent retrospective study proved that a decline of TT and cFT predicted for a poor prognosis in SARS-CoV-2 infected men [16] . In this study, we want to test the hypothesis that the prognosis of SARS-CoV-2 infection can be independently related to sex-hormones blood concentration, in particular testosterone (T) and estradiol (E).

The aim of this study was to investigate the association between sex hormones and SARS-CoV-2 infection severity. Furthermore, the associations between hormones and markers of systemic inflammation, as well as viral shedding and length of patients' hospitalization were studied. A total of 48 adult male patients, aged between 18 and 65 years and, admitted to the hospital with a diagnosis of SARS-Cov-2 infection from 1.03.2020 to 1.05.2020, were included. The infection was documented by the positivity of a qualitative RT-PCR for SARS-CoV-2, performed on nasopharyngeal swab, at the time of admission. The cases group was composed by 24 patients that developed a severe pneumonia, the majority with a framework of acute respiratory distress syndrome (ARDS) according to Berlin definition [6] . We considered severe pneumonia as the simultaneous presence of: 1) Pressure of Arterial Oxygen to Fractional Inspired Oxygen Concentration (PaO2/FiO2) < 250 mmHg and 2) the need of high flow oxygen ventilatory support by non-intensive ventilation (NIV) or mechanical ventilation during hospitalization (severe COVID-19).

The controls group was randomly selected in a 1:1 ratio, matching by ages (classes of 5 years), among patients who always maintained a PaO2/FiO2 > 300mmHg (mild COVID-19) and might have received a low-flow oxygen supplementation during the hospital stay. Of them, the 83% developed pneumonia (20/24) while the 8% did not (2/24). In 2 patients thorax CT-scan was not performed. The magnitude of the pulmonary impairment was calculated by a dedicated software (V-Lung Care by GE), considering the most affected CT-scan for each patient.

All patients were treated with the standard of care according to best evidence, local protocols and international guidelines available in that period.

The primary endpoint of our study was to compare the blood level of sex hormones between case and control groups. The secondary endpoints included the analysis of the associations between sex J o u r n a l P r e -p r o o f hormones blood levels with: i. the markers of systemic inflammation, ii. the presence of hyperinflammatory syndrome, iii. the percentage of damaged lung volume, iv. the length of patients' hospitalization, v. the time to swab clearance and vi. the time to orotracheal intubation (OTI)/death. The association between the damage lung and the length of viral swab clearance was also studied.

Plasma concentration of the following parameters were tested for each patient at the time of hospital admission: total testosterone (T), 5α-dihydrotestosterone (DHT), androstenedione (∆4), estradiol (E), prostatic specific antigen (PSA), sexual hormone binding globulin (SHBG) and albumin. PSA, SHBG, ∆4, T levels were dosed by chemiliminescence immunoassays analyser (CLIA). E was dosed by the mean of a direct immunoassay, while DHT by an enzyme-linked immunosorbent assay (ELISA). As noticed, testosterone circulates in plasma free for approximately 2 -3%, binds to SHBG and weakly binds to nonspecific proteins, such as albumin. The SHBG-bound fraction is biologically inactive because of the high binding affinity of SHBG for testosterone. The Bioavailable Testosterone (BioT) includes free plus weakly bound to albumin [24] and were derived from Total Testosterone (TT). Calculated Free Testosterone (cFT) was determined from TT through the Vermeulen formula [16] . Hence, we identified an "inflammatory phenotype" described by the presence of at least three of the following characteristics at the most impaired blood test collected: 1) lymphocytes count < 1000 cells/mmc; 2) ferritin >500 ng/mL; 3) lactate dehydrogenase (LDH) > 300 U/L; 4) D-dimer>1000 ng/mL; 5) C-reactive protein (CRP) > 3mg/dL. The duration of the viral shedding was considered from the symptoms onset to the first negative nasopharyngeal molecular test for SARS-CoV-2.The time to OTI/death was calculated from the hospital admission to the first occurrence of OTI and/or death.

The comparisons between case and control groups were performed using Chi-Square for categorical variables and Mann-Whitney for continuous parameters. The correlation between TT, cFT, BioT and the selected blood markers for severe disease (i.e. lymphocytes count, neutrophil count, ferritin, LDH, D-dimer, CRP, potassium), as well as the percentage of damaged lung volume and the length of hospitalization, were tested using Spearman rank correlation coefficient (rho). The plasma hormones levels of patients presenting or not the hyperinflammatory syndrome, were compared by the Mann-Whitney test.

Finally, the Cox regression was used to investigate the association between sexual hormones levels and the time to viral swab clearance and the time to OTI/death. All statistical analyses were performed with Stata version 15.1.

Clinical and demographic characteristics of the study population are shown in table 1.

The median age was 51 for controls group and 50 for cases group. Even if the number of patients without comorbidities were similar between the two study groups, patients with multi-morbidities were more frequent in the cases group (29.2%) compared to controls group (8.3%) (p=0.035).

The median number of days between symptoms onset and hospital admission was 9 in both groups.

The proportion of injured lung was higher in case patients than in control patients (respectively 25.1% and 12%; p=0.075), as reflected in respiratory parameters. The worst PaO2/FiO2 reached during hospitalization was 141 mmHg for cases group and 419 mmHg for controls group (p<0.001),

indeed. According to the need of oxygen supplementation: the whole cases group deserved oxygen supplementation versus 20.8% of controls (p<0.001); 62.5% of cases developed ARDS, while none of controls did (p<0.001). The majority of the patients were treated with the association of hydroxychloroquine and HIV protease inhibitors. The use of immunomodulant therapies and steroids were highly predominant in cases compared with controls (p<0.001).

Prognosis and duration of viral shedding were poorer in cases than in controls. In fact, the 100% (n=24) of control patients were cured and discharged and none of them were admitted to Intensive Care Unit (ICU). Conversely, 33.3% (8/24) of cases deserved an ICU admission (p=0.002).

Moreover, 28.8% (5/24) of cases underwent OTI and 2/24 (8.3%) died (p=0.149). Cases patients presented a median viral shedding of 20 vs 13.5 days for control patients (p=0.079); the median length of hospitalization was 23 days for cases and 9 days for controls (p<0.001).

Laboratory markers of severe disease were extremely more prevalent in case patients: during the hospitalization, the 91.7% of cases had an hyperinflammed phenotype compared with the 13.6% of controls (Table 2) . Therefore, apart from age, as expected, cases and controls group identified different clinical, radiological and laboratory features.

The differences in sexual hormones serum concentrations at the hospital admission, between the study populations, are shown in Table 3 . Testosterone was the only sexual hormone that showed a J o u r n a l P r e -p r o o f significant difference between cases and controls. Both TT, cFT and BioT levels were lower in cases than in controls ( Figure 1 ). The median value of TT in severe patients was 1.4 ng/mL (IQR 0.7 to 2.8) and 3.5 ng/mL (IQR 2.2 to 4.2; p=0.005) in mild infected patients; the median value of BioT in severe patients was 0.49 (IQR 0.30 to 1.42) and 1.21 in mild infected patients (IQR 0.87 to 1.78; p=0.008); the median value of cFT in severe patients was 0.029 ng/mL (IQR 0.016-0.068) and 0.058 ng/mL (IQR 0.035-0-081; p=0.015) in the other group. Interestingly TT level achieved a so low value, that secondary transitory hypogonadism, according to Mayo clinic laboratories reference values, was present in 66.7% of cases and 29.2% of controls (p=0.009) [31] . The concentration of the other sexual hormones did not show significant differences between mild and severe COVID-

The associations between TT, cFT, BioT and the development of a hyperinflammatory syndrome are shown in Figure 2 . As can be seen, the median TT was significantly lower in patients that developed a hyperinflammatory syndrome with respect to those who showed a low inflammatory response [1.7 ng/mL (IQR 0.80 to 2.60) vs 3. 

This single centre, retrospective, case-control study identified low testosterone serum levels as related to a more severe infection by SARS-CoV-2 virus. In contrast, 5α-DHT, ∆4, E, IGF-1, PSA, did not show any correlation to the disease's severity. Our study also showed that low TT value is significantly related to hyperinflammatory response (p=0.018) as well to some blood severity markers: LDH (rho= -0.49; p<0.001); ferritin value (rho= -0.34; p=0.032); lymphocyte count (rho= 0.31; p=0.038). The derived testosterones, cFT and BioT, presented the same performance, with less consistence. As expected, both low TT (spearman -28; p=0.052), low cFT (spearman -30; p=0.041) and BioT (spearman -33; p=0.023), resulted associated to a longer length of stay.

These findings are in accord with a retrospective study conducted by Rastrelli et al. [16] over 31 male patients with COVID-19 admitted to a sub intensive respiratory department, that showed as J o u r n a l P r e -p r o o f both TT and cFT had a significant and progressive decline according to worsening outcomes in SARS-CoV-2 infected men. It was observed a steep increase in ICU transfer and mortality risk in men with TT < 5 nmol/L or cFT < 100 pmol/L. In agreement with our findings, TT and cFT showed a negative significant correlation with biochemical risk factors (i.e, the neutrophil count, LDH, and procalcitonin, CRP, ferritin) and a positive association with the lymphocyte count [16] . Logically, the only parameter that presented a correlation with the time of swab clearance was the proportion of the healthy lung volume (spearman -0.58; p<0.001).

Several epidemiological studies revealed a difference in severity of COVID-19 by gender, without a prevalence gap [7, 9, 10] . That aspect was previously observed for SARS-CoV, MERS-CoV, HCoV-299E, H7N9 and H1N1 viruses [29] . It may find his biological explanation primarily in the role of TMPRSS2 receptor, a serin-protease expressed over the surface of type II pneumocytes and of other epithelial cells (e.g. gut, prostate, pancreas, lives and kidney). TMPRSS2 receptor has a key role in SARS-CoV-2 infection: first TMPRSS2 primes the virus spike protein, with the consequences of activating it for direct virus-cell fusion and reducing viral recognition by neutralizing antibodies; second TMPRSS2 promotes the endocytosis of the virus in the target cell by the cleavage, and the consequent activation, of ACE2 receptor [25] .

Interestingly, the androgen receptor is the main activator of transcription of the TMPRSS2 gene in humans [12, 22] . Accordingly, androgen sensitivity, that is determinate by haplotypes of the androgen receptor and their expressivity, can explain racial and inter-individual susceptibility to a J o u r n a l P r e -p r o o f severe SARS-CoV-2 infection [1] . This assumption is supported by the observation that androgenetic alopecia, a phenotypic expression of an androgen-dependent trait, seems to predispose to severe COVID-19 symptoms [23, 26] and by the less severe COVID-19 clinical picture before puberty [19] . Instead, evidences over the infection risk in prostate cancer patients receiving androgen deprivation therapy (ADT) are conflicting [14] . Accordingly, the inhibition of transmembrane protease serine 2 (TMPRSS2) activity by Camostat has been studying in 21 clinical trials to date and anti-androgen treatment with Proxalutamide improve prognosis for patients with mild-moderate COVID-19 [3] .

Unexpectedly, a recent study did not show an impactful discrepancy between sex in the TMPRSS2 proteins expression in human lung secretory cells and club cells, by gender. However, a higher TMPRSS2 and ACE2 co-expression was detected in male pneumocytes I/II compared with female cells. So, mainly the interaction between the two receptors could be a significant contributors to sex biasness [21] . It has been proved that Testosterone enhances, transcriptionally and posttranslationally ACE2 levels [4] , while oestrogen under-expresses it [10] . In addition, the female sex hormones and the immune stimulatory genes present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 over males with complex neuro-endocrinoimmunology mechanisms [4] . Our data revealed no differences of mean oestrogen blood levels between Controls and Cases [30 pg/mL (95% CI, 25 to 34) vs 28 pg/mL (95% CI, 25 to 37); p=0.959], but probably the mechanism could act at an epigenetic level.

Considering the premises, it can be expected that more severe COVID-19 will present a higher serum testosterone concentration. Actually, in our study, happened exactly the opposite.

One of the possible explanations for that finding is that a transient status of primary hypogonadism can develop as a consequence of the direct damage of the testis epithelium by the SARS-CoV-2 virus [5, 21] . Genetic and immunoblot analysis indicating that ACE2 and TMPRSS2 are highly expressed over the surface of testis cells, indeed [5, 21] . This theory is also supported by a Chinese J o u r n a l P r e -p r o o f study conducted over 81 male covid-19 patients, that showed a reducing-trend of total testosterone in the serum of the infected patients compare to general population, matched for ages [11] . Another possible explication is that low testosterone levels could be one of the expressions of the complex interaction between the host and the virus, which, through the effectors of hyper-inflammatory syndrome, may alter the central regulation of gonadal function. In the study of Ling Ma et al. [11] it can be noticed that the ratio of T to LH and the ratio of follicle stimulating hormone (FSH) to LH were dramatically decreased in males with COVID-19, as a marker of transient hypogonadism. A fall of testosterone serum levels have been documented in some non-infective acute syndrome, such as myocardial infarction, with a non clear causal mechanism, supporting a pro-trombotic state [15] .

Curiously, in those COVID-patients, neither semen parameters nor existence of SARS-CoV-2 in semen was detected, which are more straightforward evidence for testes injury caused by SARS-

Probably other local mechanism can co-operate to reduce steroidogenesis during SARS-CoV-2 infection. For example, as reported for Avian H7N9 [13] , local high level of some cytokines (e.g. TNF-α) may inhibit defined hormonal pathways. It is interesting to notice that low testosterone level may worsening SARS-CoV-2 infection by sustaining a pro-trombotic and pro-inflammatory conditions [15] . This is in line with our findings here that low T levels correlate with high levels of inflammatory markers.

To summarize, in our opinion, hypogonadism in most severe COVID-19 patients may be a transitory status caused by the direct testis injury by the virus. Taking in account TT, primary hypogonadism was present in 66.7% of cases and 29.2% of controls (p=0.009). While, neither cases nor controls complained symptoms of hypogonadism at the admission. This data can be overestimated, considering that 41 patients had blood sample in the early morning, while 7 in the afternoon (5 cases and 2 controls) with a balance distribution between the study groups (p=0.220).

It can be also noticed that the median value of PSA was only slightly lower in severe SARS-CoV-2 Interestingly, no correlation between sexual hormones and time to OTI/death was found. Probably it was due to the small sample size and to the low incidence of the investigated events.

This study presents several limitations. First, for his retrospective nature, that, among others inconveniences, cannot allow us to explore serum sexual hormones value before the SARS-CoV-2 contagion. Second, the evolution of testosterone serum concentration during different timing of COVID-19 infection was not studied. Third, unfortunately was not possible to taste gonadotropin levels, for the few stored plasma available. Forth, for the small size of the sample. To reduce confounders, we had prioritized to narrow the patients age spectrum and to preserve a high difference in clinical presentation between cases and controls groups.

This study presents several bias. First, low testosterone level can be an independent marker for biological immune-senescence: Zhou et al. have revealed that BioT deficiency is jointly correlated to chronic systemic inflammation [5] . Second in the condition of COVID-19, some other factors such as stress and corticosteroid therapy may also influence hypothalamic-pituitary-gonadal axis.

In conclusion, our study underlined the double role of testosterone in SARS-CoV-2 infection: a key pathogenic factor and a marker of severe pneumonia. On one side, low TT predicts for severe SARS-CoV-2 infection, is related to a longer hospital stay and to the burst of the hyperinflammatory syndrome, probably for the direct damage to the testis. On the other side, testosterone sensitivity is an important subjective and inter-racial key factor for affecting the infection course of Further studies are needed to deeply understand the complexity of SARS-CoV-2 pathogenesis.

J o u r n a l P r e -p r o o f ° Hyperinflammation was defined as the presence of at least three of the following characteristics at the most impaired blood test during the hospitalization: 1) lympocytes count < 1000 cells/mmc, 2) ferritin >500ng/mL, 3) LDH> 300 U/L, 4) D-dimer>1000 ng/mL, 5) C-reactive protein> 3mg/dL. Comparison of serum level of Total Testosterone, calculated Free Testosterone and Bioavailable Testosterone according to the presence of the hyperinflammatory syndrome.

p=0.018 p=0.048 p=0.020

Correlation between Total Testosterone and the serum inflammatory markers.

p=0.038 p=0.032

p=<0.001 p=0.003

* Correspondig author: Marta Camici, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Via Portuense 292, 00149

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Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Correlation between Total Testosterone, calculated Free Testosterone, Bioavailable testosterone and the length of hospital stay.p=0.052 p=0.041 p=0.023