key: cord-0976660-v61qjd6w
authors: Cinislioglu, Ahmet Emre; Cinislioglu, Nazan; Demirdogen, Saban Oguz; Sam, Emre; Akkas, Fatih; Altay, Mehmet Sefa; Utlu, Mustafa; Sen, Irem Akin; Yildirim, Fatih; Kartal, Seyfi; Aydin, Hasan Riza; Karabulut, Ibrahim; Ozbey, Isa
title: The relationship of serum testosterone levels with the clinical course and prognosis of COVID‐19 disease in male patients: A prospective study
date: 2021-08-02
journal: Andrology
DOI: 10.1111/andr.13081
sha: e305334d4133ecb86282a825d6a4996e36ced888
doc_id: 976660
cord_uid: v61qjd6w

BACKGROUND: A potential role of testosterone among sex hormones has been hypothesized in identifying sex‐related differences in the clinical consequences of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Due to the high global prevalence of hypogonadism, the relationship between hypogonadism and SARS‐CoV‐2 infection outcomes deserves an in‐depth study. OBJECTIVE: The present study aimed to investigate the relationship of serum testosterone with other laboratory parameters on the prognosis of coronavirus disease‐19 (COVID‐19) in male patients with COVID‐19 diagnosis. MATERIALS AND METHODS: This prospective cohort study included 358 male patients diagnosed with COVID‐19 and 92 COVID‐19 negative patients admitted to the urology outpatient clinics as a control group. The COVID‐19 patients were divided into groups according to prognosis (mild‐moderate and severe group), lung involvement in chest computed tomography (<50% and >50%), intensive care unit needs, and survival. RESULTS: The measured serum total testosterone level of the COVID‐19 patients group was found to be significantly lower than that of the control group (median, 140 ng/dl; range, 0.21–328, 322 ng/dl; range, median, 125–674, p < 0.001, respectively). The serum TT levels were statistically significantly lower in severe COVID‐19 patients compared to mild‐moderate COVID‐19 patients (median, 85.1 ng/dl; range, 0.21–532, median, 315 ng/dl; range, 0.88–486, p < 0.001, respectively), in COVID‐19 patients in need of intensive care compared to COVID‐19 patients who did not need intensive care (median, 64.0 ng/dl; range, 0.21–337, median, 286 ng/dl; range, 0.88–532 p < 0.001, respectively), and in COVID‐19 patients who died compared to survivors (median, 82.9 ng/dl; range, 2.63–165, median, 166 ng/dl; range, 0.21–532, p < 0.001, respectively). DISCUSSION AND CONCLUSION: Our data are compatible with low TT levels playing a role on the pathogenesis of the disease in Covid‐19 patients with poor prognosis and a mortal course and may guide clinicians in determining the clinical course of the disease.

In December 2019, a series of pneumonia cases of unknown etiology were observed in Wuhan, a city in China's Hubei province. 1 It was later stated that this pneumonia was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease was identified as coronavirus disease-2019 (COVID-19). 2 The virus has spread around the world very fast, and in March 2020, the World Health Organization (WHO) declared the COVID-19 outbreak as a global pandemic. 3 Gender-related COVID-19 mortality is one of the most frequently reported epidemiological data, and it has been shown in post-COVID- 19 outbreak studies that the disease is more severe and fatal in men, potentially due to gender-related immunological response and additional factors. 4 Various social factors, genetic, immunological, hormonal differences, and lifestyle habits (i.e., smoking and alcohol consumption) are thought to play a role in this gender disparity in the prognosis of the disease. 5 A potential role of testosterone among sex hormones has been hypothesized in identifying sex-related differences in the clinical consequences of SARS-CoV-2 infection. 6 Studies have shown that the serum total testosterone (TT) levels are decreased due to aging and in the presence of comorbidities such as obesity, diabetes mellitus, and cardiovascular diseases, which are quite common in SARS-CoV-2 patients. 7 Due to the high global prevalence of hypogonadism (estimated to be 15%-20% among middle-aged/elderly men), the relationship between hypogonadism and SARS-CoV-2 infection outcomes deserves an in-depth study. 6, 8, 9 In line with all these scientific studies, in this cohort study, we aimed to investigate the serum testosterone level and its relationship with other laboratory parameters on COVID-19 prognosis in male patients diagnosed with COVID-19.

Ethics committee approval was obtained from the Ataturk University to the urology outpatient clinics of the same centers between the same dates. The control group included 92 male patients in total, who were compatible with the patient group in terms of age and gender.

Informed consent was obtained from all patients included in the study. 

The patients were divided into two groups as mild/moderate and severe patient groups according to the prognosis criteria published in the guide titled "COVID- 

SARS-CoV-2 infection was confirmed using pharyngeal and/or nasal swab positivity (RT-PCR). Positive radiological findings of SARS-CoV-2 infection (unilateral or bilateral ground glass images, parenchymal consolidation) in the thorax computed tomography (CT) (Toshiba Aquilion 64 CT Scanners) were recorded.

Categorical data were presented as numbers and percentages. 

The blood samples of the patients were collected on a voluntary basis, and the volunteer information form was read and signed by the patient or their relative as consent form. Venous serum samples were obtained from each patient diagnosed with COVID-19 in a tube of at least 5 ml on the first day of hospitalization. Sera were collected between 7 and 11 o'clock in the morning to measure the TT, FSH, and the LH levels considering the circadian rhythm. These hormones were measured using the chemiluminescence immunoassay method (Siemens Atellica Reagent) in both centers (Erzurum Regional Training and Research Hospital and Trabzon Kanuni Training and Research Hospital). Hypogonadism was accepted as a serum TT level of <300 ng/dl, which is the cut-off value of the American Urological Association (AUA). 10 

The Table 2 .

While the median duration of hospitalization of patients diagnosed with COVID-19 was 6 (range, 2-18) days, it was found to be 13 (range, 3-45) days in patients who needed an intensive care unit. A significant negative correlation was observed between the serum TT level and the length of stay in the hospital. In addition, a significant negative correlation was found between the serum TT level of the patients followed in the intensive care unit and the length of stay in the intensive care unit (Table 3) .

While a statistically significant negative correlation was observed between the serum TT level and serum DD, lactate dehydrogenase (LDH), C-reactive protein (CRP), and ferritin levels, a significant positive correlation was determined with the lymphocyte levels. Furthermore, while a significant negative correlation was observed between the TT:LH ratio measured in patients and the serum DD, LDH, CRP and ferritin levels, a significant positive correlation was found with the lymphocyte levels ( Table 5 . The ACE2 enzyme has been shown to be a potential receptor for SARS-CoV-2, and independent studies have shown that one of the tissues in which the ACE2 enzyme is expressed most is the testicles. [12] [13] [14] Similar to the results of this study, we found that the serum FSH and LH levels of male patients diagnosed with COVID-19 were higher than the control group. In addition, we determined that the TT:LH ratio, in their androgen receptors were determined to predict the intensive care need in COVID-19-infected males. In addition, consistent with the known anti-inflammatory effect of testosterone, the CRP levels were shown to increase in male patients with long polyQ and above 60 years of age. A tendency toward hypogonadism was reported in males with repetitive long polyQ. In that study, which explained the variability in COVID-19 severity with the differences in the host genome, males with polyQ alleles were reported to have a tendency toward hypogonadism;

these patients had a poorer prognosis, and the CRP levels were higher in these patients. The results of that study are consistent with those of ours, which indicate that the serum TT levels and the disease prognosis are associated, and this may explain the pathophysiology of this association at genomic level. 16 The plasma testosterone concentration is known to decrease with comorbidities such as age, obesity, diabetes, hypertension, coronary artery disease (CAD), and chronic obstructive pulmonary disease (COPD), and these comorbidities are known to be quite common in COVID-19 patients. 17, 18 In the meta-analysis conducted by Balasubramanian et al, it was reported that the prevalence of hypogonadism in men with COPD ranged between 22% and 69%

and that hypogonadism was associated with many other systemic diseases, including osteoporosis, depression, and muscle weakness. 19 In the study by Montaño et al, the testosterone levels were shown to be associated with higher FEV1 (volume of air exhaled in the 1st second of forced expiration) and forced vital capacity in men, and high testosterone levels contributed to better lung function in men, and low testosterone levels were found to cause a decrease in respiratory muscle activity and exercise capacity. 20 In addition, in the random- 22 Various studies in both animals and humans have shown that hypogonadism is associated with increased pro-inflammatory cytokines, and TRT decreases the IL-1, IL-6, and TNF-a. 23 In the study conducted by Mohamad et al, testosterone was reported to have antiinflammatory effects in vivo, and this was linked to mainly two observations; the first being that testosterone deficiency is associated with increased inflammatory cytokine levels, and the second observation being that TRT reduces the inflammatory cytokine levels. 24 In our study, we compared men diagnosed with COVID-19 according to the severity of their lung involvement, and we found that the serum TT levels and the TT:LH ratios of patients with severe lung involvement were significantly lower than those of patients with mild involvement.

Considering the studies conducted on the effects of low testosterone levels on the lungs in the literature, it does not seem surprising that patients with low TT levels had extensive lung involvement in our study.

Hypogonadism can make older men more prone to progression of atherosclerosis. 25 For these reasons, it is thought that low total and free testosterone levels, especially in elderly male patients, may be responsible for deaths related to CAD. 26 The results of our study suggests that decreased TT levels may play an important role in the pathogenesis of the disease in men diagnosed with COVID-19 who have a poor prognosis, who need intensive care, and who have a mortal course. Although there are studies reporting that men with prostate cancer with COVID-19 who received androgen deprivation therapy had a milder disease than those who did not, our study does not support these findings. 30, 31 However, we believe that the results of our study support the pathophysiological mechanisms between COVID-19 and low testosterone levels. However, COVID-19 may affect the testicles as well as other organs. For this reason, the primary affected Leydig cell function and reduced testosterone level may also be merely a marker of the disease. Despite the presence of studies on the relationship between the serum testosterone level and the prognosis of the disease in male patients with COVID-19 diagnosis in the literature review, this study will take its place in the literature as a prospective study with the largest volume, including a control group.

The limitations of the study are that it did not include men diagnosed with COVID-19 who did not have determined testosterone levels prior to the diagnosis, absence of long-term results of testosterone levels after the diagnosis, absence of patients in need of intensive care unit without COVID-19 diagnosis in the same period, and not measuring the ACE2 receptor concentration levels of the patients.

In addition, in this study, TRT could not be given to patients due to ethical and scientific concerns, and whether or TRT was effective in 

Our data are compatible with low TT levels playing a role on the patho- 

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The authors have declared that no conflict of interest exists.

Ahmet Emre Cinislioglu performed the evidence synthesis, wrote the original draft, and revised and edited the manuscript. Nazan