Abstract
Abstract
Objective
To investigate effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected male patients.
Methods
This prospective cohort study included 221 consecutive male patients (>18 years old) with laboratory confirmed SARS-CoV-2 who had been hospitalized due to COVID-19. The patients were divided into 3 groups: Asymptomatic patients (n: 46), symptomatic patients who were hospitalized in the internal medicine unit (IMU) (n: 129), and patients who were hospitalized in the intensive care unit (ICU) (n: 46).
Results
As serum total testosterone level at baseline decreases, probability (%) to be in the ICU significantly increases (p = 0.001). As serum total testosterone level at baseline decreases, probability (%) of mortality significantly increases (p = 0.002). In the patients who had pre-COVID-19 serum gonadal hormones test (n: 24), serum total testosterone level significantly decreased from pre-COVID-19 level of 458 ± 198 ng/dl to 315 ± 120 ng/dl at the time of COVID-19 in the patients (p = 0.003).
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.
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is a systemic disease, affecting respiratory, cardiovascular, gastrointestinal, neurologic and urogenital systems. It may mainly cause acute respiratory distress syndrome, leading to relatively high risk of death [1,2]. Since the World Health Organization has declared the disease as pandemics, globally as of 29 July 2020, a total of 16,558,289 SARS-CoV-2 cases have been confirmed, and 656,093 people died due to COVID-19 (https://covid19.who.int).
The mortality rate due to COVID-19 has been ranged from 0.9% in patients without comorbidities to 10.5% in patients with co-morbid diseases (https://covid19.who.int). Higher mortality rate related to SARS-CoV-2 has led clinicians to investigate newer parameters that might predict prognosis of COVID-19. Male sex has been reported as a worse clinical outcome than women in some studies, suggesting the presence of a male-related susceptibility in COVID-19. In addition, global average life expectancy has been reported as 5.1 years less for men than for women [3].
Testosterone is the principal male sex hormone, and decreases on average by 0.8–2% per year after the age of 40 years. The prevalence of male hypogonadism has been ranged from 2.1 to 9.5% in men aged 40–70 years [4–6]. Its rate significantly increases, ranging 10–80% in several morbid diseases [4–6]. Male late-onset hypogonadism has been reported as a risk factor for diabetes, chronic obstructive pulmonary disease, metabolic syndrome, dyslipidemia, thrombotic and cardiovascular disease, leading to increased mortality in the general population [6–10]. The prevalence of hypogonadism in age hospitalized male patients has been reported as 53.3% [7]. Low levels of testosterone have been found as an association with higher rates of infection-related hospitalization and all-cause mortality in male hemodialysis and intensive care unit patients [6,7,11,12]. In a double blind, placebo controlled, randomized study, testosterone replacement therapy provided improvement in peak oxygen consumption in elderly patients with chronic heart failure [13].
Angiotensin-converting enzyme 2 (ACE2) is primarily expressed in the adult type Leydig and Sertoli cells, and has an important role in lung protection [14,15]. Therefore, viral binding to the ACE2 receptor may decrease its expression causing deterioration in a lung protective pathway, and might affect testosterone production, leading to increases in pro-inflammatory cytokines in SARS-CoV-2 infected patients [16]. Very few studies have investigated the relationship between testosterone and mortality with the contradictory results in patients with COVID-19 with a small sample size and short follow-up period [12,17].
Our hypothesis was whether serum testosterone and other gonadal hormones might play an important role on the prognosis of COVID-19 in male patients. Therefore, the aim of this cohort study was to investigate effect of serum testosterone and its relationship with other laboratory parameters on the prognosis of COVID-19 in SARS-CoV-2 infected male patients.
Materials and methods
Patients and data collection
During an interval between 20 April and 8 May 2020, 3766 consecutive people were tested for COVID-19 in 2 hospitals (Mersin City Educational and Research Hospital and University of Mersin School of Medicine Hospital) in Mersin province, Turkey. Of those, SARS-CoV-2 was detected in 438 (11.63%). Therefore, 438 consecutive patients with laboratory confirmed SARS-CoV-2 were hospitalized due to COVID-19. Of the patients, 418 were adults (221 males and 197 females, >18 years old), and 20 were children (11 boys and 9 girls). Therefore, the study included 221 consecutive male patients (>18 years old) with laboratory confirmed SARS-CoV-2 who had been hospitalized due to COVID-19. At the beginning, all the 221 male patients with laboratory confirmed SARS-CoV-2 were hospitalized in the internal medicine unit to monitor and complete a detailed clinical history, complete physical examination, laboratory and radiological imaging studies. Of the patients, 46 were asymptomatic on the second or third day of the admission, and these patients were discharged from the hospital. The rest 175 patients were symptomatic and remained hospitalized. Therefore, all the adult male patients were divided into three groups: Asymptomatic patients (n: 46), symptomatic patients who were hospitalized in the internal medicine unit (IMU) (n: 129), and patients who were hospitalized in the intensive care unit (ICU) (n: 46).
All data were prospectively collected. A detailed clinical history, complete physical examination, laboratory and radiological imaging studies were performed in every patient. All data of the patients were checked and reviewed by the two physicians (BS and MU). All deaths during hospitalization were recorded. The study was approved by the local ethics committee, consisting of the members from the Turkish Ministry of Health and University of Mersin School of Medicine (2020/#378). An informed consent was taken from all patients, included in the study.
Demographic characteristics, co-morbidities, laboratory results, radiological and computer tomographic (CT) scan findings, admission to the ICU, days in the ICU and duration of hospital stay were recorded in every patient. Charlson’s comorbidity index (CCI) which predicts 10-year survival in patients with multiple comorbidities were measured in all patients [18].
The criteria for discharge were absence of fever for at least 2–3 days, substantial improvement in both lungs on the chest CT scan, clinical remission of respiratory symptoms, and two throat-swab samples negative for SARS-CoV-2 RNA, obtained at least 24 h apart.
Of the patients, 24 had measurement of total testosterone level at any time with any reason in the last one year before COVID-19 pandemics, and had the second measurement at the time of diagnosis of COVID-19. In the patients who had pre-COVID-19 serum gonadal hormones test (n: 24), the total testosterone level was compared from pre-COVID-19 to the time of COVID-19.
Laboratory evaluation
All laboratory tests were performed on the first day the patients were admitted to the hospitals, and these values were used for the statistical calculations. Considering the circadian rhythm of testosterone release, venous serum samples were obtained in the morning (7–11 a.m.) to determine serum follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol (E2) and total testosterone levels in every patient, on the first day of the admission to the hospital. These hormones were measured by a chemiluminescence immunoassay (Siemens Healthcare Diagnostics Inc, Laboratory Diagnostics, Advia Centaur XPT, Erlangen, Germany, produced in Ireland). Other laboratory biochemical tests, taken from venous blood, included blood count, coagulation profile, C-reactive protein (CRP), D-dimer, procalcitonin, total white blood cells (WBC), neutrophils, lymphocytes, platelets, creatinine, alanine transaminase (ALT), aspartate-transaminase (AST), lactate dehydrogenase (LDH), ferritin, troponin, fibrinogen and albumin. Blood sample analyses were performed in the central laboratory of the two hospitals with commercially available kits which are used for the clinical practice of the hospitals.
Definitions of criteria for diagnosis of COVID-19
Pharyngeal and/or nose swab positivity of SARS-CoV-2 infection was confirmed using real-time PCR. Fever was defined as axillary temperature of at least 37.3 °C.
On chest computer tomographic (CT) scan (GE Healthcare Optima CT660, Chicago, IL, USA), positive radiological findings, related to SARS-CoV-2 infection were considered in the presence of any finding or findings such as bilateral or unilateral opacities with or without pleural effusion, multiple ground-glass opacity (accompanied or not by septal thickening) and parenchymal consolidation in the lungs of the patients [1,2,19].
One or more of clinical symptoms, related to COVID-19, such as fever, cough with or without sputum, muscle aches and/or fatigue, dyspnea, headache, sore throat and gastrointestinal symptoms were considered as positive clinical symptom(s). Asymptomatic situation was considered as no any clinical symptom in the presence of positive SARS-CoV-2 infection.
Definition of criteria for diagnosis of hypogonadism
Hypogonadism was considered as the presence of serum total testosterone level of <300 ng/dl [4,20].
Testing for SARS-CoV-2
Real-time reverse transcription polymerase chain reaction (RT-PCR) assay nucleic acid amplification test was used to directly with Bio-Speedy COVID-19 RT-qPCR kit BS-SY-WCOR-305-1000; version 2003261000SK-MK for detecting SARS-CoV-2 RNA. This method’s sensitivity was 99.4%, and the specificity was 99%.
For detecting SARS-CoV-2 RNA, nasopharyngeal specimens were collected from suspected patients, and placed into the collection tube. Materials were sent to the laboratory immediately. Total RNA was extracted about two hours for respiratory sample RNA isolation kit (Wuhan, China). A cycle threshold value less than 37 was defined as a positive result, and cycle threshold value 40 or more was defined as a negative test. The cycle threshold value within 37–40 was defined as needed a retest.
Assessment of sexual functions
In the asymptomatic patients (n: 46), sexual functions were assessed using the nationally validated international index of erectile function-erectile function domain (IIEF-EF) questionnaire, including 6 questions (based on a total score of 30) [21]. The IIEF-EF score of ≥26 was considered as normal sexual function, and the IIEF-EF score of <26 was considered as the presence of erectile dysfunction. The aging male symptom (AMS) questionnaire was used to assess testosterone deficiency symptoms. In addition, presence of sexual libido was assessed face to face, and the answer was recorded as “yes” or “no.”
Statistical analysis
For statistical analyses SPSS® (Statistical Package for the Social Sciences Inc, Chicago, IL, USA) version 21.0 package program was employed, and p values less than 0.05 was considered to be statistically significant. Descriptive statistics for continuous variables were expressed, and also tabulated as mean ± standard deviation, and for categorical variables as frequencies, and percentages (%).
T-test and Mann–Whitney U tests were used to compare duration of hospitalization between the groups.
One-way ANOVA test was used to compare mean age, BMI, CCI score and serum gonadal hormones including FSH, LH, total testosterone, prolactin and estradiol levels among the groups, and the Post Hoc tests were used to compare the serum gonadal hormone mean values between the groups. The Pearson’s correlation test was used for the association between mean total testosterone and other clinical and laboratory findings.
Probability (%) to be in the ICU and mortality during hospitalization were calculated using Linear and logarithmic equations. Multivariate and univariate analyses were used to investigate all the parameters that might predict to be in the ICU and mortality. The Odds ratio with 95% confidence interval (CI) was used to predict prognosis of COVID-19, such as probability to be in the ICU and mortality during hospitalization.
The chi-square test was used to compare mortality rates between the genders. Paired t test was used to compare serum total testosterone level from pre-COVID-19 to the time of COVID-19 in the patients who had pre-COVID-19 serum gonadal hormones test.
Results
Of the 438 consecutive patients with laboratory confirmed SARS-CoV-2 who had been hospitalized due to COVID-19, the gender representation was male in 232 (53%) and female in 206 (47%). The mean age of the adult male patients was 45.07 ± 18.28 years (range: 19–88). The mean age of the adult female patients was 44.04 ± 18.8 years (range: 19–98). The mean age of the children was 8.02 ± 5.6 years (range 0–18) (9.86 ± 5.09 for boys and 6.77 ± 5.69 for girls). Of the 438 consecutive patients, death was observed in 11 of the male adult patients (4.97%) and 7 of the female patients (3.55%), revealing no significance between the two genders (p > 0.05). However, none died in the children group.
The mainly symptoms were fever in 95 (43%), and respiratory symptoms such as cough, sputum and dyspnea in 94 (42.5%), and other symptoms such as myalgia, fatigue, diarrhea, nausea or vomiting in 102 (46.1%). Chest CT scans showed positive findings in 125 (56.6%) of the patients. The mean BMI was 23.77 ± 3.45 (range: 18.17–33.03). The CCI score was 0 in 125 (56.6%), 1 in 16 (7.2%) and ≥2 in 80 (36.2%) of the patients.
Table 1 shows mean age, BMI and CCI score of the patients according to the groups. As shown in the table, significant differences were observed in the mean age (p = 0.000) and CCI score (p = 0.000), however, no significant differences in BMI (p = 0.676) among the 3 groups.
Table 1. Mean age, BMI and CCI score of the patients according to the groups.
Hypogonadism was observed in 113 (51.1%) of the male patients. Of the hypogonadal patients, serum total testosterone level was between 200 and ≤300 ng/dl in 62 patients, between 100 and ≤200 ng/dl in 25 patients and ≤100 ng/dl in 26 patients. Of the eugonadal patients, serum total testosterone level was between 300 and ≤400 ng/dl in 51 patients, between 400 and ≤500 ng/dl in 26 patients, 500 and ≤600 ng/dl in 22 patients and ≥600 ng/dl in 9 patients.
Among the 46 patients with COVID-19 who stayed in the ICU, 11 (23.9%) remained staying in the ICU (intubated: 8), and 35 (76.1%) were taken to the IMU. Of the patients in the ICU, 11 (23.9%) died at the end of the study. Of the symptomatic patients who were discharged from the IMU, the mean hospital stay was 5.84 ± 4.09 days (range 1–24). Of the patients who stayed in the ICU, the mean duration was 11.24 ± 6.54 days (3–32), revealing significant difference between the IMU and ICU groups (p = 0.000). The mortality was observed in 11 (4.97%) of all patients.
Of the 46 male patients with COVID-19 who were asymptomatic, 30 (65.2%) had loss of libido. In this group, the mean IIEF-EF score was 18.85 ± 9.96 (1–30), and the mean AMS score was 22.18 ± 2.97 (17–61).
Table 2 shows laboratory findings of all patients with COVID-19. Table 3 shows serum gonadal hormone levels of the patients according to groups in the COVID-19 patients. As shown in Figure 1, mean total testosterone decreased, and mean gonadotropins (FSH and LH) increased, as the severity of the COVID-19 increased. The mean total testosterone level was significantly lower in the ICU group than in the asymptomatic group (p = 0.006). In addition, the mean total testosterone level was significantly lower in the ICU group than in the IMU group (p = 0.017). The mean FSH level was significantly higher in the ICU group than in the asymptomatic group (p = 0.02).
Published online:
03 September 2020Figure 1. Mean serum gonadal hormone levels of the COVID-19 patients according to the groups: (A) FSH, (B) LH, (C) total testosterone, (D) prolactin and (E) estradiol.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/itam20/2020/itam20.v023.i05/13685538.2020.1807930/20210528/images/medium/itam_a_1807930_f0001_c.jpg"})
Figure 1. Mean serum gonadal hormone levels of the COVID-19 patients according to the groups: (A) FSH, (B) LH, (C) total testosterone, (D) prolactin and (E) estradiol.
Table 2. Laboratory findings of all male patients with COVID-19.
Table 3. Serum gonadal hormone levels of the COVID-19 patients according to groups.
Table 4 shows comparison of mean total testosterone levels in the presence of various findings and parameters in the COVID-19 patients. The mean total testosterone level was significantly lower in the presence of CCI score of ≥2 than in the presence of CCI score of 0 and 1 (p = 0.001). The patients in the ICU group showed significantly lower mean total testosterone level than the patients who were not in the ICU (p = 0.001). The patients who died showed significantly lower mean total testosterone than the patients who were alive (p = 0.001). The patients with D-dimer level of ≥1 mg/ml showed significantly lower mean total testosterone level than the patients with D dimer level of <1 mg/ml (p = 0.009).
Table 4. Comparison of mean total testosterone levels in the presence of various findings and parameters in the COVID-19 patients.
The Pearson correlation analysis showed that increased age (r = −0.236, p = 0.000), increased levels of D-dimer (r = −0.213, p = 0.003), LH (r = 0.171, p = 0.01), CRP (r = −0.144, p = 0.003) and procalcitonin (r= −0.225, p = 0.000) were the parameters that might predict lower total testosterone level.
Figure 2 shows probability (%) to be in the ICU during hospitalization in the COVID-19 patients. Of the 46 patients in the ICU group, 35 (76%) had serum total testosterone level of <300 ng/dl, while 21 (45.6%) had serum total testosterone level of <200 ng/dl. As serum total testosterone level at baseline decreases, probability (%) to be in the ICU during hospitalization significantly increases (p = 0.001 for linear equation and 0.000 for logarithmic equation).
Published online:
03 September 2020Figure 2. Probability (%) to be in the ICU during hospitalization in the COVID-19 patients.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/itam20/2020/itam20.v023.i05/13685538.2020.1807930/20210528/images/medium/itam_a_1807930_f0002_c.jpg"})
Figure 2. Probability (%) to be in the ICU during hospitalization in the COVID-19 patients.
Figure 3 shows probability (%) of mortality during hospitalization in the COVID-19 patients. Of the 11 deaths, 10 (90.9%) had serum total testosterone level of <300 ng/dl, while 8 (72.7%) had serum total testosterone level of <200 ng/dl at baseline. As serum total testosterone level at baseline decreased, probability (%) of mortality significantly increased (p = 0.002 for linear equation and 0.000 for logarithmic equation).
Published online:
03 September 2020Figure 3. Probability (%) of mortality during hospitalization in the COVID-19 patients.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/itam20/2020/itam20.v023.i05/13685538.2020.1807930/20210528/images/medium/itam_a_1807930_f0003_c.jpg"})
Figure 3. Probability (%) of mortality during hospitalization in the COVID-19 patients.
On the multivariate analysis of the demographic and clinical characteristics and laboratory findings that might predict to be in the ICU in the COVID-19 patients, presence of D-dimer ≥1 mg/l was the only highly significant predictor for the ICU in the COVID-19 patients (OR: 7.309, 95% CI: 1.241–43.058). On the univariate analysis, older age (OR: 1.046), longer hospitalization (OR: 1.225), lower albumin level (OR: 0.631), lower total testosterone level (OR: 0.996), presence of fever (OR: 2.236), positive chest CT findings (OR: 3.005), presence of D-dimer ≥1 mg/l (OR: 14.065) and presence of CCI ≥2 (OR: 2.318) were the highly significant predictors for the ICU in the COVID-19 patients.
On the multivariate analysis of the demographic and clinical characteristics and laboratory findings that might predict mortality in the COVID-19 patients, no parameter was significant predictor for the mortality. However, on the univariate analysis, longer hospitalization (OR: 1.118), lower albumin level (OR: 2.188), lower total testosterone level (OR: 1.008), presence of fever (OR: 6.488), presence of D-dimer ≥1 mg/l (OR: 15.750) were the highly significant predictors for the mortality in the COVID-19 patients.
In the patients who had pre-COVID-19 serum gonadal hormones test (n: 24), serum total testosterone level significantly decreased from pre-COVID-19 level of 458 ± 198 ng/dl to 315 ± 120 ng/dl at the time of COVID-19 in the patients (p = 0.003).
Discussion
Some risk factors in multivariate analyses have been reported about staying in the ICU and the mortality for adult patients with COVID-19. Pathophysiologic mechanisms that might be associated with the dead of patients with COVID-19 include increasing the neutrophil count, D-dimer, blood urea and creatinine levels and decreasing in lymphocyte counts [1]. Neutrophilia may be related to cytokine storm induced by virus invasion, coagulation activation might be related to sustained inflammatory response, and acute kidney injury might be related to direct effects of the virus, hypoxia and shock [1]. In the present study, logistic regression analysis showed that older age, longer hospitalization, lower albumin level, lower total testosterone level, presence of fever, positive chest CT findings, presence of D-dimer ≥1 mg/l and presence of CCI ≥2 were the highly significant predictors for the ICU in the COVID-19 patients. In addition, longer hospitalization, lower albumin level, lower total testosterone level, presence of fever, presence of D-dimer ≥1 mg/l were the highly significant predictors for the mortality in the COVID-19 patients.
Sex specific differences in disease severity of COVID-19 have been studied in various diseases including cardiovascular diseases and infectious agents [22,23]. The incidence of COVID-19 has ranged from 54 to 69% of the males from the study population [1,22,23]. In addition, in a prospective cohort study, the incidence of age-standardized all-cause mortality was found as significantly higher in men than in the women (7.4 per 1000 person-years for men and 4.5 per 1000 person-years for women [23]. There are some studies reporting that MERS-COV and SARS-COV have infected more men than women [24,25]. In a mice study, Channappanavar et al. [25] showed that male mice were more susceptible to SARS-CoV infection, compared with age-matched females. In a meta-analysis consisting of 10 studies with 1994 patients, Li et al. [22] reported COVID-19 patients’ clinical characteristics, discharge rate and fatality, and they found that the male took a significantly larger percentage in the gender distribution of COVID-19 patients (60%) with the fatality rate of 5%. Nakashima et al. [11] reported the association between serum testosterone levels and adverse clinical outcomes such as events and all-cause mortality in male dialysis patients, and they found that infection related hospitalization was more frequent in the lower testosterone tertile than in the higher testosterone tertile. In addition, all-cause mortality was significantly greater in the lower testosterone tertile than in the higher testosterone tertile. In the present study, we did not observe significant sex related difference in mortality rate between adult men (4.97%) and women (3.55%), although the rate was slightly higher in the males than in the females.
Late-onset hypogonadism or testosterone deficiency may result in significant detriment to quality of life, and adversely affect the function of multiple organ systems [4]. In a systematic review and meta-analysis, consisting of the 21 studies, Araujo et al. [6] demonstrated that difference in the means of the top and bottom third of the standard normal distribution in total testosterone was associated with 35 and 25% increased risk of all-cause and cardiovascular disease mortality, respectively. Iglesias et al. [7] reported the prevalence of hypogonadism as 53.3% in 150 male aged ≥ 65 years hospitalized patients for acute diseases. The main cause of hospitalization was respiratory tract infection in 23.7% of in hypogonadal patients. They also found significant association between low serum total testosterone level and mortality during hospital stay. In a study, supporting the theory of higher mortality in hypogonadal men, exogenous testosterone treatment was associated with decreased mortality compared with no testosterone treatment [26]. Prevalence of hypogonadism in men with chronic obstructive pulmonary disease ranges from 22 to 69% and has been associated with several other systemic conditions including osteoporosis, depression and muscle weakness [9]. Hypogonadism associated systemic diseases have been more prevalent in obese patients. Iglesias et al. [7] demonstrated that patients with low/normal weight (BMI < 25 kg/m2) who died during hospitalization showed significant lower testosterone level than those who survived. In the present study, hypogonadism (serum total testosterone level of <300 ng/dl) was observed in 51.1% of the male patients.
Testosterone is associated with the immune system of respiratory organs, and low levels of testosterone might increase the risk of respiratory infections. The metallopeptidase, Angiotensin-converting enzyme 2 (ACE2) is a constitutive product of adult type Leydig and Sertoli cells, and has an important role in lung protection [14,15]. ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into the epithelial respiratory cells and myocardium [27]. Therefore, viral binding to the ACE2 receptor may decrease its expression causing deterioration in a lung protective pathway, and might affect testosterone production, leading to increases in pro-inflammatory cytokines in SARS-CoV-2 infected patients [16]. Measuring testosterone levels may be recommended at the time of COVID-19 diagnosis. There are also contradictory studies suggesting that the hyperandrogenic phenotype could explain the COVID-19 positivity in those few young males with severe SARS-CoV-2 infection [20], possibly with shorter AR CAG lengths, who are greater risk of developing prostate cancer because higher receptor transcription activity [28]. Montopoli et al. [17] demonstrated that cancer patients have an increased risk of SARS-CoV-2 infections than non-cancer patients. They included 118 patients with prostate cancer, and demonstrated that patients receiving androgen deprivation therapy (n: 4) had a significantly lower risk of SARS-CoV-2 infection compared to patients who did not receive androgen deprivation therapy (n: 114). However, they had only 4 patients under androgen deprivation therapy, and attempted to compare those 4 patients with 114 patients who did not receive androgen deprivation therapy [17].
Rastrelli et al. [12] included 31 consecutive male patients with COVID-19 who recovered in the ICU of a hospital in Italy. They demonstrated that lower baseline levels of total testosterone and calculated free testosterone levels predicted poor prognosis and mortality in the SARS-CoV-2 infected patients who admitted to intensive care unit. They also found that both total testosterone and calculated free testosterone levels showed a negative significant correlation with the neutrophil count, LDH and procalcitonin, but a positive association with the lymphocyte count. In addition, total testosterone was also negatively associated with CRP and ferritin levels. However, the number of patients included in their study was limited, clinical findings of the patients were not included, and they included only patients in the ICU, and were unable to compare those findings with the SARS-CoV-2 infected patients who were asymptomatic or symptomatic who were in the IMU, not in the ICU. In our study, of the 46 patients in the ICU group, 76% had serum total testosterone level of <300 ng/dl, while 45.6% had serum total testosterone level of <200 ng/dl. As serum total testosterone level at baseline decreased, probability (%) to be in the ICU during hospitalization significantly increased. In addition, of the 11 deaths in our study, 10 (90.9%) had serum total testosterone level of <300 ng/dl, while 8 (72.7%) had serum total testosterone level of <200 ng/dl at baseline. As serum total testosterone level at baseline decreased, probability (%) of mortality significantly increased. In the present study, we did not include measurement of free testosterone level, because the American Urological Association (AUA) guidelines do not recommend routine use of free testosterone measurements in clinical decision making [19].
As the limitation of the study, we did not include a control group, consisting of the patients other than COVID-19. However, during the COVID-19 pandemics, it is very hard to include patients without COVID-19 in the IMU and ICU at the same period. Therefore, we did not want to use historical control group at the different time period (for example before COVID-19 period). In addition, checking the concentration of ACE2 would be worth in the COVID-19 patient population to investigate relationship with the total testosterone level. Unfortunately, we were unable to check this measurement. These could be aim of other studies in the future.
Conclusions
For the first time, our data suggest that 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. Future studies related to testosterone treatment in this population would discover possible improvement in clinical outcomes with the testosterone treatment in SARS-CoV-2 infected hypogonadal male patients.
| Asymptomatic group (n: 46) mean ± SD (range) | IMU group (n: 129) mean ± SD (range) | ICU group (n: 46) mean ± SD (range) | p Value (ANOVA test) | |
|---|---|---|---|---|
| Age (year) | 34.83 ± 12.51 (19–79) | 44.54 ± 17.63 (19–88) | 56.8 ± 18.57 (19–88) | 0.000 |
| BMI | 23.87 ± 3.6 (18.17–30.89) | 23.62 ± 3.6 (18.17–33.03) | 24.18 ± 2.83 (19.01–30.89 | 0.676 |
| CCI score | 0.46 ± 1.09 (0–4) | 1.35 ± 1.95 (0–11) | 1.33 ± 1.99 (0–10) | 0.000 |
| Parameters | Mean | Standard Deviation | Minimum | Maximum |
|---|---|---|---|---|
| FSH (mIU/ml) | 6.639 | 3.39 | 1.34 | 18.21 |
| LH (mIU/ml) | 5.679 | 2.38 | 1.19 | 12.01 |
| Total testosterone (ng/dl) | 308 | 164 | 18 | 931 |
| Prolactin (pg/ml) | 9.749 | 4.75 | 1.91 | 33.60 |
| Estradiol (pg/ml) | 25.85 | 9.90 | 11.79 | 65.76 |
| Albumin (mg/l) | 3.569 | 0.78968 | 2.00 | 7.14 |
| White blood cell (WBC) | 9199 | 4181.80 | 2990 | 26,000 |
| Neutrophil (/l) | 6119 | 4037.50 | 1680 | 22,000 |
| Creatinine (µmol/ml) | 1.07 | 0.78 | 0.32 | 5.86 |
| Alanine aminotransferase (ALT) (U/l) | 39.70 | 35.41 | 4 | 271 |
| Aspartate aminotransferase (AST) (U/l) | 47.02 | 43.75 | 5 | 256 |
| C-reactive protein (CRP) (mg/l) | 295.93 | 323.32 | 104 | 2452 |
| Lactate dehydrogenase (LDH) (mU/l) | 15.80 | 36.36 | 0.10 | 238 |
| Procalcitonin (µg/l) | 0.88 | 2.90 | 0.10 | 25.48 |
| D-dimer (mg/l) | 0.968 | 1.23 | 0.02 | 7.16 |
| Ferritin (µg/l) | 168.04 | 287.46 | 0.02 | 1681 |
| Troponin (ng/ml) | 71.38 | 237.04 | 0.10 | 2377 |
| Fibrinogen (g/l) | 407.92 | 208.08 | 34 | 1026 |
| Gonadal hormones | Asymptomatic group (n: 46) (mean ± SD) | IMU group (n: 129) (mean ± SD) | ICU group (n: 46) (mean ± SD) | p Value (Post Hoc)* |
|---|---|---|---|---|
| FSH (mIU/ml) | 5.26 ± 2.68 | 6.67 ± 3.22 | 8.41 ± 4.38 | Asymptomatic vs IMU: 0.222 Asymptomatic vs ICU: 0.02 IIMU vs ICU: 0.176 |
| LH (mIU/ml) | 5.31 ± 2.38 | 5.73 ± 2.22 | 5.97 ± 3.17 | Asymptomatic vs IMU: 0.758 Asymptomatic vs ICU: 0.699 IIMU vs ICU: 0.935 |
| Total testosterone (ng/dl) | 346 ± 140 | 318 ± 156 | 241 ± 191 | Asymptomatic vs IMU: 0.563 Asymptomatic vs ICU: 0.006 IIMU vs ICU: 0.017 |
| Prolactin (pg/ml) | 8.71 ± 3.80 | 9.81 ± 3.96 | 11.05 ± 8.65 | Asymptomatic vs IMU: 0.625 Asymptomatic vs ICU: 0.346 IIMU vs ICU: 0.662 |
| Estradiol (pg/ml) | 26.18 ± 7.31 | 25.71 ± 9.70 | 26.1 ± 14.32 | Asymptomatic vs IMU: 0.982 Asymptomatic vs ICU: 1.000 IIMU vs ICU: 0.991 |
*Tukey HSD.
| Presence | Mean (ng/dl) | Standard deviation | p Value | |
|---|---|---|---|---|
| Symptoms | + | 344.78 | 140.02 | 0.058 |
| – | 298.18 | 168.91 | ||
| Fever | + | 290.36 | 179.59 | 0.179 |
| – | 321.10 | 150.810 | ||
| Respiratory findings | + | 306.46 | 167.88 | 0.912 |
| – | 308.93 | 161.93 | ||
| Chest CT findings | + | 294.69 | 169.94 | 0.173 |
| – | 325.05 | 155.41 | ||
| CCI score | ≥2 | 257.45 | 161.88 | 0.001 |
| 0 and 1 | 336.50 | 158.93 | ||
| ICU | + | 239.94 | 187.88 | 0.001 |
| – | 326.73 | 152.18 | ||
| Intubation | + | 195.13 | 183.14 | 0.048 |
| – | 312.11 | 162.31 | ||
| Death | + | 158.45 | 151.68 | 0.001 |
| – | 315.70 | 161.29 | ||
| D-dimer (mg/l) | ≥1 | 224.33 | 215.08 | 0.009 |
| <1 | 343.10 | 141.67 |
Disclosure statement
The authors report no declarations of interest.
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