Transient Hypogonadism Induced by SARS-CoV-2 during COVID-19 in Men Aged under 65 Years ()
1. Introduction
Although COVID-19 is a disease with respiratory onset, it may evolve to a systemic level with multi-organ involvement thus accounting for its variable symptomatology. The clinical manifestations of SARS-CoV-2 infection appear to be broad, ranging from asymptomatic infection, mild upper respiratory tract disease, to severe viral pneumonia with respiratory failure during the 2nd or 3rd week of infection [1]. SARS-CoV-2 infects pulmonary alveolar epithelial cells using the angiotensin-converting enzyme 2 (ACE2) receptor as its entry receptor [2]. ACE2 is also a constituent product of Leydig and Sertoli cells in the adult testis. Thus, the presence of this ACE2 receptor in both cells could favor tropism of SARS-CoV-2 for testicular tissue, suggest possible involvement of the testis during COVID-19 and hence its effect on testosterone production in infected men [3]. In addition, there is evidence that the entire population with SARS-CoV-2 is predominantly male. This trend could be attributed to a more responsive and robust immune system in women, due to estrogen modulating the immune system to protect women from severe inflammation [4]. The interest of this work was to determine the impact of COVID-19 on testicular function and assess its association with disease severity.
2. Methodology
2.1. Type of Study
We conducted a descriptive and analytical cross-sectional study at the COVID-19 unit of the Yaoundé Central Hospital in Cameroon. The study was conducted over a period of 5 months, from May 2020 to September 2020.
Inclusion criteria: We included men confirmed positive for SARS-CoV2 and aged between 21 and 65 years who gave their informed consent.
Exclusion criteria: Any subject with known hypogonadism or on therapy that may affect gonadal function was excluded.
Sampling was consecutive, exhaustive and non-probability.
2.2. Procedure
Patient information was obtained from the medical records of the included patients. We recorded age, sex, comorbidities, clinical presentation, room air oxygen saturation, and initiation of oxygen therapy. Patients were seen twice during the study: during and 2 months after infection. During these two phases, patients were sampled at 8:00 am for total testosterone and SHBG by competitive ELISA and Sandwich ELISA, respectively, according to laboratory procedures.
The biological data were interpreted as follows:
Total testosterone ranging from 3 - 12 ng/ml in adult males was considered to have normal gonadal function. Patients with a serum total testosterone value of less than 3 ng/ml were considered to have true hypogonadism. SHBG values were defined according to the standards set by the French Urology Agency, with normal values ranging from 13 - 71 nmol/l in adult men. We considered any patient above this standard as having relative hypogonadism [5].
2.3. Statistical Analyses
Data were processed and analyzed using SPSS version 26.0 and Excel. Descriptive analyses were used for socio-demographic data and clinical characteristics. Quantitative variables were expressed as means, with standard deviation. For the study of correlations, we first classified the patients into 2 groups according to the severity of the infection: one group under oxygen therapy and the other without oxygen therapy. Then we looked for correlations between SHBG and testosterone of the patients using Spearman’s Rho correlation. The threshold of statistical significance was set at a value of p < 0.05. We obtained an ethical clearance from the Institutional Research and Ethics Committee of the Université des Montagnes (2020/057/UdM/PR/CIE).
3. Results
At inclusion 40 patients gave their informed consent to participate in the study and were sampled during infection. Two months after infection, 8 patients responded to the call for a second follow-up sample and the remaining 32 were lost to follow-up.
1) Characteristics of the study population
The average age of the participants was 46.4 ± 11.8 years, with extremes of 22 and 63 years. The most represented age group was [36; 55] years (50%)
· Distribution of the study population according to comorbidities
The most frequent comorbidity was arterial hypertension in 15% of cases, followed by diabetes (12.5%) and finally obesity and HIV infection in equal proportions (12.5%).
· Distribution of patients according to clinical symptoms
During the infection, most patients experienced a decrease in libido (75%). The most frequent general symptoms were asthenia (67.5%) and fever (45%), followed by respiratory signs such as cough (60%) and finally ear, nose and throat (ENT) and digestive symptoms.
· Distribution of patients on oxygen therapy and without oxygen therapy
We had a total of 09 patients on oxygen therapy versus 31 who were not on oxygen therapy at the onset of the COVID-19 infection.
2) Biological data
· Biological values during the infection.
During infection, mean total testosterone was 11 ± 2.4 ng/ml with a minimum of 4.6 ng/ml and a maximum of 27 ng/ml and the median at 11 ng/ml. The mean SHBG was 113 ± 66.9 nmol/l, with a minimum of 16.5 and a maximum of 283.7 nmol/l and a median during infection increased to 115.7 nmol/l. However, 34/40 patients had an increased SHBG compared to the threshold value (Table 1 and Table 2).
· Biological values 2 months after infection:
Eight of the 40 participants at inclusion were reviewed after infection. Median total testosterone increased from 11 ng/ml during infection to 12.7 ng/ml after infection.
Median SHBG during infection decreased from 115.7 nmol/l to 82 nmol/l after infection (Figure 1 and Figure 2).
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Table 1. Total testosterone and SHBG levels within the study population.
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Table 2. Total testosterone and SHBG levels within the study population.
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Figure 1. Comparison of testosterone levels during and after infection (n = 8).
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Figure 2. Comparison of SHBG levels during and after infection (n = 8).
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Table 3. Correlation between SHBG and testosterone in patients with oxygen.
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Table 4. Correlation between SHBG and testosterone in patients without oxygen.
3) Correlation study
· Correlation between SHBG and testosterone in oxygen-treated patients
There was a statistically significant (P = 0.04), moderate positive correlation between serum testosterone and SHBG levels in oxygen-treated patients (Table 3).
· Correlation between SHBG and testosterone in non-oxygenated patients
There was no statistically significant correlation between SHBG and testosterone in patients who had not been on oxygen therapy (Table 4).
4. Discussion
The aim of the study was to evaluate the impact of COVID-19 on testicular function in a group of men aged 21 - 65 years. During the study 40 patients were recruited and only 8 agreed to return for a check-up 2 months after infection. In addition, we were unable to have a control population to compare testosterone levels in healthy versus affected patients. It should be noted that the study was conducted during the 1st wave of SARS-CoV-2 infection. Many of the patients reported to be cured as well as the uninfected individuals did not want to have any further contact with the hospital setting. This high drop-out rate could be a limitation for the assessment of gonadal function after infection, but the value of 8 participants already gives us a trend of this evolution. In our study, each participant was his own control. Our results show that the mean total testosterone level of the study population was 11.08 ± 2.48 ng/ml with a minimum of 4.60 and a maximum of 27. While the mean SHBG was 113 ± 66.93 nmol/ml with a minimum of 16.50 and a maximum of 283.75. However, 34 patients in the sample had increased SHBG compared to the reference value of 13 - 71 nmol/l according to the French Society of Urology [5]. When comparing 08 participants who were reviewed after infection, we observed that median total testosterone decreased during infection (11 ng/ml) and increased after infection (12.7 ng/ml).
In contrast to studies that described a low free testosterone levels among men with severe forms of COVID 19 [6], free testosterone levels remained within normal levels in our study. Notwithstanding this finding, the free testosterone levels dropped during infection as compared to the post-infection control (P = 0.028).
Although these values remained at non-pathological thresholds, this result was statistically significant (P = 0.028). SHBG during infection was increased (115.7 nmol/l) and after infection was decreased (82 nmol/l) but still remained at a pathological threshold. There was a positive correlation between total testosterone and SHBG in patients on oxygen while in the absence of oxygen therapy there was no correlation between total testosterone and SHBG.
Regarding the gonadal function of our patients, although the mean testosterone was normal, 34 patients had an increased SHBG of more than 71 nmol/L. This is because SHBG, the sex steroid transporter protein, binds with high affinity to testosterone and consequently decreases the free fraction, which is the active form and is responsible for the effects of testosterone on the cells of the body. Thus, an increase in SHBG to the 71 nmo/l threshold will be considered as a state of hypogonadism in our patients, as attested by the French Urological Association [5]. Likewise, a retrospective study carried out in Wuhan in 2020 on a population of men infected with SARS-Cov-2 showed an increased level of LH, with a normal plasma testosterone level but a significantly reduced testosterone/LH ratio. These results suggested to the authors an early stage of primary hypogonadism [7]. This is because at an early stage, abnormal testicular production of testosterone can stimulate the release of LH to temporarily maintain testosterone levels.
We also established correlations between SHBG and testosterone in patients who were on oxygen therapy. There was a statistically significant (P = 0.04) and positive correlation between serum total testosterone and SHBG levels in patients who had been on oxygen therapy. Meaning that the more severe the disease, requiring oxygen, the higher the SHBG and total testosterone and the lower free active testosterone. These observations are consistent with those of Cayang et al. [8] who found that as serum total testosterone levels decreased, the likelihood of the patient being in the intensive care unit increased significantly, same as the likelihood of mortality. Furthermore, this decrease in testosterone secretion could be explained by the fact that SARS-CoV-2 enters and infects Leydig cells using angiotensin converting enzyme 2 (ACE2) which is a constituent product of adult Leydig cells, and therefore decreases testosterone secretion as demonstrated by Hoffman et al. [2].
On the contrary, Van Zeggeren et al. in Amsterdam reported that lower levels of total and free testosterone were associated with fatal outcome in men who died of COVID-19, as were lower levels of SHBG in both men and women in a retrospective study including 40 patients [9].
Furthermore, a study by Maggio et al. indicates that pro-inflammatory cytokines, notably IL-6, IL-1 beta and TNF alpha, inhibit testosterone secretion through their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis. This gives a clue to the state of hypogonadism that could occur during COVID-19 infection as a result of the cytokine storm observed during this condition [10] [11]. This inflammatory state resulting from the cytokine storm, and its deleterious effect impact on testosterone secretion, could justify the reactive increase of SHBG during this infection, as was the case in our study population.
5. Conclusion
The high SHBG values found during SARS-CoV-2 infection could suggest a possible relative and transient hypogonadism without true alteration of the intra testicular testosterone production which occurs all the more in severe forms. This phenomenon, which seems to improve after infection, could be attributed to the inflammatory state present during COVID-19.
Abbreviations
ACE2 Angiotensin 2 Converting Enzyme
RNA Ribonucleic Acid
COVID-19 Coronavirus Disease 2019
OD Optical Density
ELISA Enzyme Linked Immunosorbent Assay
FSH Follicle Stimulating Hormone
HTN High Blood Pressure
LH Luteinizing Hormone
WHO World Health Organization
PAD Diastolic Blood Pressure
PAS Systolic Blood Pressure
RT-PCR Real Time Polymerase Chain Reaction
SaO2 Oxygen Saturation
SHBG Sex Hormone Binding Globulin
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus Type 2