Introduction:
In early December 2019, a new contagious disease were identified in China (1) and
caused by as a novel beta coronavirus (2) that has currently been named severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) (3). It causes respiratory illness
named by World Health Organization as coronavirus disease 2019 (COVID-19) and has
become a global viral pandemic and a public health problem of international concern
(4).
The SARS-CoV-2 infection presents with a broad clinical spectrum, including asymptomatic
infection, mild upper respiratory tract infection, to a life-threatening multi-organ
failure. This broad clinical presentation is an evidence of the multiple targets of
SARS-CoV-2 including digestive, cardiovascular, urinary systems (5, 6, 7). Similar
to SARS, SARS-CoV-2 recognizes the N-terminal peptidase domain of angiotensin converting
enzyme 2 (ACE2) at the surface of the cell membrane using the S domain and invade
the host (8). Based on this relationship between ACE2 and SARS-CoV-2, the susceptibility
of SARS-CoV-2 infection is higher in any cells expressing ACE2. Meng-Yuan et al. demonstrated
that the ACE2 protein had high expression level in testis, kidney, small intestine,
heart, thyroid and adipose tissue (9). (10). Wang ZP et al. analyzed scRNA-seq datasets
obtained from Gene Expression Omnibus and Sequence Read Archive, and showed that ACE2
is highly expressed in spermatogonia, Leydig and Sertoli cells (11). As a consequence,
testicular tissue may be a target tissue of SARS-CoV-2. After the binding of SARS-CoV-2
to ACE2 and virion membrane fusion, downregulation of ACE2 expression leads to excessive
production of angiotensin by the related enzyme ACE (12). A previous study showed
that increased replication of coronaviruses downregulate the expression of ACE2 (13).
Overproduction of angiotensin enhances oxidative stress mechanisms and leads to tissue
injury. In sum, these findings may explain the possibility of harmful effects of SARS-CoV-2
on testis, potentially affecting TT secretion. In analogy to this relationship, it
has been shown that the testis may be the target organ for other viruses, including
human immunodeficiency virus, mumps, Zika and Ebola causing orchitis, and occasionally
decreased TT production and oligospermia (14).
Acute respiratory infection is another cause of decreased serum total testosterone
(TT) levels. Muehlenbein MP et al. hypothesized that TT levels decreases during acute
infection and they evaluated patients with respiratory tract infection (15). The cases
of their study experienced 10% lower salivary TT levels during respiratory tract infection
compared with recovered period. In another study by Iglesias P et al., the authors
evaluated serum TT levels in hospitalized patients (16). Their results demonstrated
that serum TT levels were associated with respiratory tract infection and were significantly
lower in patients with respiratory tract infection. Moreover, the main cause of hospitalization
of hypogonadic patients was respiratory tract infection.
The present study aimed to compare male reproductive hormones such as TT, luteinizing
hormone (LH), follicle stimulant hormone (FSH) and prolactin between patients with
COVID-19, age-matched cases with non-COVID-19 respiratory tract infection and age-matched
controls.
Material and Methods:
Study design:
This study was reviewed and approved by institutional ethics committee, on 27 April
2020 and complied with the Declaration of Helsinki. The information for all patients
including demographic data, clinical characteristics, laboratory parameters and outcomes,
were collected prospectively. Two authors independently reviewed the data collection
forms to ensure that there was no duplicated information. Data were analyzed and interpreted
by the authors.
Study population:
The study population comprised three groups including patients hospitalized for COVID-19,
hospitalized cases with non-COVID-19 respiratory tract infection between 22 March
and 22 May 2020 and age-matched controls admitted to the urology outpatient department
before January 2020. The first group was patients with COVID-19, the second groups
included patients with non-COVID-19 respiratory tract infection, and the third consisted
of control cases admitted to urologic outpatient clinic for reproductive function
evaluation.
The first inclusion criteria for whole groups was age between 18 and 65 years. Additional
inclusion criteria for group-1 were (1) positive reverse-transcription polymerase
chain reaction (RT-PCR) test of nasal and pharyngeal swab specimens (2) typical chest
CT findings including ground-glass opacities, particularly on peripheral and lower
lobes, crazy paving and bilateral multiple lobular and subsegmental areas of consolidation.
Patients with non-COVID-19 respiratory tract infection had final diagnosis of at least
two negative RT-PCR tests and negative chest CT findings. The exclusion criteria for
all study subjects were (1) previous exposure to exogenous testosterone, 5-alpha reductase
inhibitors, luteinizing hormone–releasing hormone agonists, dehydroepiandesterone,
clomiphene citrate, or other selective estrogen receptor modulators (2) use of opioid
drugs within 3 months prior to study (3) diagnosis of prolactinoma and any cancer
(4) history of testicular diseases and surgical interventions known to affect sex
hormone levels.
Nasal and pharyngeal swab specimens were collected for the COVID-19 test on the day
of admission. RT-PCR assay was used according to the manufacturer’s instructions.
The degree of severity (mild, moderate, and severe) were determined according to the
COVID-19 Treatment Guidelines published by the National Institutes of Health (17).
Clinical, Laboratory and Imaging Parameters:
The recent medical history, clinical symptoms or signs on admission were extracted
from electronic medical records. Radiologic assessments included CT, and all laboratory
testing was performed according to the clinical care needs of the patient. Laboratory
assessments were drawn before any treatment the first morning after admission between
8-11 am, after an overnight fast, and consisted of a blood count, C-reactive protein
(CRP), procalcitonin (PCT), D-dimer and fibrinogen. After analyzing of blood samples
for routine tests required for group-1 and group-2 patients’ needs, the residual serum
samples were collected for male hormone profiles detection. The data of serum TT,
FSH, LH and prolactin levels were retrieved from the medical records kept in the hospital.
Laboratory analyses were performed in the central laboratory of the hospital with
commercially available kits normally used for clinical practice of the hospital. The
presence of a radiologic abnormality on the basis of the documentation or description
in medical charts was determined.
Definitions:
Testosterone deficiency was defined as < 300 ng/dL according to American Urological
Association testosterone deficiency guideline (18). Compensated or subclinical hypogonadism
was defined as low-normal TT levels (> 300 ng/dL) and elevated LH (> 9.4 IU/L) according
to European Male Aging Study criteria (19).
Outcomes:
The primary outcome of the study was detection of the difference of TT, FSH, LH and
prolactin levels between the groups. Secondary outcome was to correlate TT and hospitalization
time and oxygen saturation on hospital admission (SpO2) of patients.
Statistical Analysis:
Sample size calculation was based on changes in serum TT levels. Type I error α was
0.05, type II error β was 0.10, two-tailed P-value was <0.05, study and control group
ratio was 1:1, loss to follow-up rate was 10%, and at least 90 patients in each group
were studied in the final analysis. Data were checked for suitability for a normal
distribution with the Shapiro Wilk test and expressed as mean (SD) or median [interquartile
range (IQR)] values when they did not show a normal distribution or percentage for
continuous and categorical variables, respectively. Variables were compared between
groups by using the Fisher exact test or chi-square test for categorical variables.
Kruskal Wallis test with Bonferroni correction was used for multiple and pairwise
comparisons, for continuous variables. Pearson’s correlation test was used for investigating
relationship between continuous variables. All analyses were performed by STATA, version
14 (Stata Corp., College Station, TX, USA). For all the statistical analyses, p<0.05
was considered significant.
Results:
Demographics and Characteristics of the Study Population:
Baseline demographic and clinical characteristics for the patients with COVID-19 (n=89),
those with non-COVID-19 respiratory tract infection (n=30) and those with neither
COVID-19 nor respiratory tract infection (n=143) presented in Table-1. Mean age of
the study population was 50.28±9.8 years (20-65 years). The mean age of study groups
was 49.9±12.5 years, 52.7±9.6 years and 50±7.8 years, respectively. Cases in three
study groups were similar of age (p=0.06).
Clinical characteristics of COVID-19 patients:
Eighty nine cases infected with COVID-19 were studied (Table-1). Fever (54%) and cough
(49.4%) were the most common symptoms. Thirty cases (33.7%) had shortness of breath.
Moreover, 29 (32.6%) patients had myalgia, 12 patients (13.5%) had sore throat, and
8 patients (18.56%) had chest pain symptoms. During the diagnostic procedure by RT-PCR,
we found that 77 patients (86.5%) got a positive result in the first test, 12 patients
(13.5%) got a positive result in the second test.
Among 89 patients with COVID-19, 52.8% (47/89) were diagnosed as “mild type”, 33.7%
(30/89) as “moderate type”, and 13.5% (12/89) as “severe type”.
Clinical characteristics of patients with non-COVID-19 respiratory tract infection:
Thirty patients had non-COVID-19 respiratory tract infection were studied (Table-1).
Fever (46.7%) and dyspnea (40%) were the most common symptoms. Seven cases (23.3%)
had chest pain and 7 cases (23.3%) had cough. Also, 5 (16.6%) patients had myalgia,
3 patients (10%) had sore throat symptoms, and 2 (6.6%) had diarrhea. Twenty-one patients
had two negative RT-PCR, 8 patients had 3 negative RT-PCR tests, and one patient had
5 negative RT-PCR test. All patients with non-COVID-19 respiratory tract infection
had non-specific CT findings.
Comparison of inflammation parameters of study groups:
The clinical presentation of patients with COVID-19 and patients with non-COVID-19
respiratory tract infection was similar (p=0.14) (Table-1
). Only the COVID-19 patients had more cough symptom than other group (p=0.018). The
comparison of inflammation parameters are presented in Table-2. The white blood cell
count of the COVID-19 group (median 6.08 109/L, IQR 3.36 109/L) was significantly
lower than that of the non-COVID-19 respiratory tract infection (median 8.71 109/L,
IQR 4.98 109/L) and control group (median 7.7 109/L, IQR 2.52 109/L) (p=0.0001). It
was not different between non-COVID-19 respiratory tract infection and control group
(p=0.07). The lymphocyte count in the COVID-19 group (median 1.4 109/L, IQR 0.83 109/L)
was also significantly lower than that in the non-COVID-19 respiratory tract infection
(median 2.13 109/L, IQR 1.46 109/L)and control group (median 2.3 g/L, IQR 0.96 g/L)
(p=0.0001). The lymphocyte count was not different between non-COVID-19 respiratory
tract infection and control group (p=0.07).
Table-1
Demographic and clinical parameters of study groups.
Group-1 (n=89)
Group-2 (n=30)
Group-3 (n=143)
p
Age (years) (mean±SD)
49.9±12.5
52.7±9.6
50±7.8
0.06
Symptoms [n (%)]FeverCoughSore throatMyalgiaDyspneaChest painDiarrheaAnosmia
48 (54)44 (49.4)12 (13.5)29 (32.6)30 (33.7)8 (18.56)3 (3.3)2 (2.2)
14 (46.7)7 (23.3)3 (10)5 (16.6)12 (40)7 (23.3)2 (6.6)0 (0)
n/a
0.14
SD: standard deviation
Hemoglobin levels of patient and control groups were not statistically different (p=0.0574)
(Table-2
). CRP levels were significantly higher in patients with COVID-19 and non-COVID-19
respiratory tract infection than control group (p=0.0007 and p=0.03). However, COVID-19
and non-COVID-19 respiratory tract infection groups were similar in terms of CRP (p=1).
In addition, the D-dimer, procalcitonin and fibrinogen levels were not significantly
different between group-1 and group 2 (p=0.03, p=0.51 and p=0.32, respectively).
Table-2
Inflammation parameters of study groups
Group-1 (n=89)
Group-2 (n=30)
Group-3 (n=143)
p
Median Hb, g/dL
14.42±3.37
13.13±2.48
14.5±1.58
0.0574
Median (IQR) WBC, x 109/L
6.08 (3.36)
8.71 (4.98)
7.7 (2.52)
0.0001*
Median (IQR) LYM, x 109/L
1.44 (0.83)
2.13 (1.46)
2.3 (0.96)
0.0001#
Median (IQR) CRP, mg/dL
42.46 (58.97)
29.93 (68.98)
0.6 (1.81)
0.01ψ
Median (IQR) d-dimer, mg/L
0.54 (0.62)
0.86 (1.71)
n/a
0.007
Median (IQR) procalcitonin, ng/mL
0.07 (0.13)
0.07 (0.21)
n/a
0.51
Median (IQR) fibrinogen, mg/dL
496.7 (164.6)
413.15 (208.2)
n/a
0.32
Post-hoc analyses: ∗: 1 vs. 2 p<0.0001; 1vs. 3 p=0.017; 2 vs.3 p=0.07
#: 1 vs. 2 p<0.0001; 1 vs. 3 p=0.0017; 2 vs. 3 p=0.07
ψ: 1 vs. 2 p=0.31; 1 vs. 3 p=0.0065; 2 vs. 3 p=0.03
IQR: interquartile range
Comparison of hormonal level:
The comparison of TT levels showed a significant difference between the groups (p=0.0001).
Serum TT levels decreased from median 332 ng/dL in control cases to median 288.67
ng/dL in patients with non-COVID-19 respiratory tract infection to median 185.52 ng/dL
in patients with COVID-19. The proportion of patients with testosterone deficiency
in group-1, group-2 and group-3 was 74.2%, 53.3 and % 37.8, respectively (p<0.0001).
Four cases (4.5%) in COVID-19 group had compensated or subclinical hypogonadism and
only a patient in group-2 (3.33%) had this diagnosis (p=0.06). COVID-19 patients and
non-COVID-19 respiratory tract infection patients had significantly higher serum LH
(p=0.0003) and serum PRL (p=0.0007) levels compared to control cases. However, there
was not a difference between group-1 and group-2 (p=1 and p=1). When serum FSH levels
were compared, the groups had similar levels of FSH levels (p=0.91). The ratio of
LH/TT is lowest in patients with COVID-19 (Table-3
).
Table-3
Hormonal levels of study groups.
Group-1 (n=89)
Group-2 (n=30)
Group-3 (n=143)
p
Median (IQR) TT, ng/dL
185.52 (179.12)
288.67 (184.39)
332 (118)
0.0001∗
Median (IQR) LH, U/L
5.67 (4.52)
5.39 (2.46)
4.1 (2.62)
0.0002#
Median (IQR) prolactin, μg/L
9.6 (5.59)
9.61 (9.69)
7.5 (1.86)
0.0009ψ
Median (IQR) FSH, U/L
6.01 (6.17)
5.65 (6.19)
6.05 (4.85)
0.87
Median LH/T
0.03 (0.029)
0.0205 (0.051)
0.011 (0.011)
0.0001ϒ
Post-hoc analyses: ∗: 1 vs. 2 p=0.002; 1 vs. 3 p<0.0001; 2 vs. 3 p=0.04
#: 1 vs. 2 p=1; 1 vs. 3 p=0.0001; 2 vs. 3 p=0.01
ψ: 1 vs. 2 p=1; 1 vs. 3 p=0.0007; 2 vs. 3 p=0.03
ϒ: 1 vs. 2 p=0.048; 1 vs. 3 p<0.0001; 2 vs. 3 p<0.0001
IQR: interquartile range
TT: total testosterone
LH: luteinizing hormone
FSH: follicle stimulant hormone
The Impact of Severity of COVID-19 on Reproductive Hormones:
The comparison of hormone levels of COVID-19 patients classified into 3 different
groups according to disease severity presented in Table-4
. Despite the serum TT levels of patients with severe illness were lower than other
patients, this difference was not statistically different (p=0.084). However, serum
LH and FSH levels were significantly lower in the patients with severe illness (p=0.0348).
Table-4
Hormonal levels of patients classified according to the severity of the disease.
Mild
Moderate
Severe
p
Median (IQR) TT, ng/dL
203.51 (210.01)
179.61 (105.55)
82.01 (264.08)
0.0837
Median (IQR) LH, U/L
5.59 (4.3)
7.32 (4.62)
3.71 (5.71)
0.0107*
Median (IQR) prolactin, μg/L
9.05 (5.95)
10.35 (4.91)
11.55 (32.02)
0.1683
Median (IQR) FSH, U/L
5.8 (5.76)
7.59 (7.74)
3.84 (3.49)
0.0348#
Post-hoc analyses: ∗: 1 vs. 2 p=0.109; 1 vs. 3 p=0.1085; 2 vs. 3 p=0.005
#: 1 vs. 2 p=0.165; 1 vs. 3 p=0.205; 2 vs. 3 p=0.0182
IQR: interquartile range
TT: total testosterone
LH: luteinizing hormone
FSH: follicle stimulant hormone
Correlation between TT and clinical parameters of patients:
Pearson's correlation test was performed for investigating any significant relationships
between serum TT levels and hospitalization time of patients with COVID-19. Serum
TT was found to be negatively associated with hospitalization time of patients with
COVID-19 (r=-0.45, p<0.0001) (Figure-1a
). In addition, according to the results, a significant positive correlation was observed
between SpO2 and serum TT levels in patients with COVID-19 ( r=0.32, p=0.0028) (Figure-1b).
However, no significant correlations were observed between TT and hospitalization
time (Figure-1c) and SpO2 levels (Figure-1d) in patients with non-COVID-19 respiratory
tract infection (r=-0.25, p=0.21 and r =-0.077, p=0.68). Moreover, the correlation
between serum TT levels and neutrophil and lymphocyte counts and CRP levels was evaluated
and it was not detected any significant association between these parameters. In the
present study, only 4 patients with COVID-19 died and the mean levels of serum TT
of this patients (116.24) was below the median levels of patients with COVID-19.
Fig 1
:
Discussion:
To the best knowledge, despite this manuscript does not present firstly the evaluation
of reproductive hormonal levels in COVID-19 patients, it demonstrates for the first
time that lower levels of TT are presented in patients with COVID-19. Also, the serum
TT levels were compared in different groups of COVID-19 patients classified according
to the severity of illness. There was no significant decrease in serum TT levels,
even though severity of COVID-19 increased. Serum TT levels were higher in patients
with non-COVID-19 respiratory tract infection, but it was lower than controls. The
lowest LH/TT ratio was observed in patients with COVID-19. The diagnosis of testosterone
deficiency were higher in patients with COVID-19 compared to patients with non-COVID-19
respiratory tract infection and control group (p<0.00001). However, compensated or
subclinical hypogonadism was not different between (p=0.06). Moreover, serum LH and
prolactin levels were higher in patients with COVI-19 and non-COVID-19 respiratory
tract infection. Interestingly, even though the prolactin levels did not differ with
the severity of disease, the patients with severe disease had lowest LH levels in
comparison with mild and moderate disease patients. Despite of harmful influence of
SARS-CoV-2 on LH and TT levels, FSH levels did not differ between patients and control
cases. Noteworthy, this study demonstrated a positive relationship between lower TT
and longer hospitalization time, thus leading to a prediction of the progression of
the disease of patients with COVI-19. Accordingly, lower TT are significantly associated
with lower SpO2 levels at admission of patients with COVID-19. However, this relationship
was not observed in patients with non-COVID-19 respiratory tract infection, because
higher serum TT levels in this patient group compared to COVID-19 patients. Clinical
presentation of patients with COVID-19 did not differ from patients with non-COVID-19
respiratory tract infection. Both of groups presented similar symptoms on admission.
In the literature, there are several studies demonstrated that the testis is susceptible
to viral infection (20). In comparison to bacterial infections that normally target
accessory glands and epididymis, viruses that circulate in the blood primarily attack
testis. It is known that a human immunodeficiency virus (HIV), mumps virus and Zika
virus may induce reduction in testosterone production in human, feline leukemia virus
in cats and bluetongue virus in ruminants (20, 21, 22). The deleterious effects of
viruses involve the direct damage of testicular tissue, destruction of Leydig cells
and decreasing testosterone production. Puggioni et al. showed that bluetongue virus
replicated in the endothelial cells of the peritubular areas within the testis (22).
It caused to enhanced type-I interferon response, reduction in testosterone biosynthesis
by Leydig cells, and even destruction of Sertoli cells (22). However, a current study
by Ma et al. comparing the sex-related hormones between COVID-19 patients and controls
did not show any difference in serum TT and FSH levels between COVID-19 patients and
control cases (23). This result is not compatible with the findings of this study,
because of decreased serum TT and FSH levels of patients with COVID-19 compared to
age-matched males. LH
The testicular function may be effected by multiple pathogenic mechanisms occurring
during SARS-CoV-2 infection. ACE2 is highly expressed by Leydig cells and its down-expression
by SARS-CoV-2 lead to increase of angiotensin II levels (12). It has been shown that
angiotensin II reduced both basal and LH stimulated testosterone synthesis by Leydig
cells, ACE2 may modulate the production of testosterone of these cells and protect
testis by limiting angiotensin II detrimental effects (24, 25). In this context, changes
in LH and TT levels of patients were evaluated in present study and it has been determined
that patients with COVID-19 had increased levels of LH and decreased levels of TT
compared to patients with non-COVID-19 respiratory tract infection and control cases.
Moreover, the lowest LH/TT ratio was calculated in patients with COVID-19. In the
literature, several studies suggested that increased LH/TT ratio indicates Leydig
cell defects and it is an important marker of primary hypogonadism (26). Primary hypogonadism
is a result of factors having negative influence on testicular tissue such as injury,
tumor and infections. This finding supports the impact of harmful effect of SARS-CoV-2
on ACE2 expression and correspondingly increase of angiotensin II and reduction of
testosterone production.
Compensated hypogonadism is defined TT in the normal range and inappropriately high
LH (19). In European Male Aging Study including 3,369 community-dwelling middle-aged
and older men, they reported that 9.5% of the aforementioned population was classified
as compensated hypogonadism. Dutta et al presented compensated hypogonadism rates
as 12.44% in 225 patients with human immunodeficiency virus (HIV) infection (27).
The rate of compensated hypogonadism in this study was 4.5% in COVID-19 patients.
The rate of compensated hypogonadism in COVID-19 patients was lower than the study
by Dutta et al., because the disease duration of HIV patients was 40 months and this
long time may influence negatively the hormonal status of patients. However, the rate
of COVID-19 patients is based on acute phase effects of disease and the evaluation
of long term effects of COVID-19 on hormonal status may contribute to understand its
hormonal impacts.
The serum PRL level also significantly elevated in COVID-19 patients and in patients
with non-COVID-19 respiratory tract infection compared to control cases (p=0.0009).
However, this elevation reached not to levels of hyperprolactinemia. Therefore this
is not a cause of pituitary suppression and decreased TT levels. Serum PRL levels
may be influenced by stress and infection (28). In addition, cytokines IL-1, IL-2,
and IL-6 stimulate prolactin secretion (29). The increased levels of IL-1, IL-2 and
IL-6 in patients with COVI-19 has been demonstrated in several studies (30). This
relationship between increased levels of interleukins and suppression of prolactin
secretion explained the elevated levels of prolactin in patients with COVID-19.
In present study, the TT levels correlated negatively with hospitalization time (r=-0.395,
p<0.0001) and positively with SpO2 levels at admission of patients with COVID-19.
This finding demonstrates that serum TT levels is an important factor and predictor
for the clinical process of patients. Rastrelli et al. evaluated the association between
TT levels and clinical outcomes in a cohort of patients with COVID-19 (31). They demonstrated
that lower TT levels predict poor prognosis in patients with COVID-19. They correlated
TT levels with neutrophil and lymphocyte counts and CRP levels and they found a negative
correlation between serum TT levels and neutrophil count and CRP levels and a positive
correlation between TT levels and lymphocyte count. However, in the present study,
serum TT levels did not correlated with neutrophil and lymphocyte counts and CRP levels.
Testosterone deficiency is one possible cause of unexplained anemia in older men,
because of the lack of stimulating effect of testosterone on erythropoiesis. Despite
of lower levels of testosterone in patients with COVID-19, the hemoglobin levels were
not different from patients with non-COVID-19 respiratory tract infection and control
subjects. The reason for this indifference could be divided into two subjects. First
of them is long life-span of erythrocytes and short incubation period of COVID-19.
After 4-6 days incubation period, symptoms onset occurred and patients admitted to
the hospitals and were included into this study. An erythrocyte has a life-span 90-120
days in human circulation. The time interval is not enough to cause in a decrease
in hemoglobin levels. In addition, myelosuppressive chemotherapy is an important factor
for the treatment-associated anemia and this anemia is detectable at least 4-6 weeks
after this therapy due to the life-span of erythrocytes in serum (32). The second
factor is the required time for the suppression of erythropoiesis by testosterone
deficiency. The exact mechanism for the regulation of erythropoiesis by testosterone
is not fully understood. Testosterone stimulates erythrocyte production by various
mechanisms including stimulation of erythropoietin release, direct stimulatory action
on bone marrow erythroid progenitor cells via androgen receptors and iron regulatory
protein hepcidin (33). In the light of aforementioned evidences, it is not surprising
testicular deficiency leads to anemia. However, the onset of anemia needs a period
of time. Hamilton et al., presented a time span for hemoglobin reduction as 1 g/dl
after involuntary castration in 6 prisoners as 40 days. In another study of 147 prostate
cancer patients receiving combined androgen blockage, hemoglobin levels decreased
in all patients from a mean baseline of 14.9 g/dL to means of 13.9 at 1 month (34).
With these findings, the indifference of hemoglobin levels between patient and control
groups is logical.
This study has several strengths. The study provides the evidence about the alteration
of male reproductive hormones under COVID-19. In this study, serum LH and prolactin
levels significantly elevated and serum TT levels decreased in COVID-19 patients,
which infer to the potential hypogonadism. Because greater portion of patients with
COVID-19 were reproductive-aged, cases, who recovered from this disease, should be
evaluated with hormonal tests to detect harmful effects of SARS-CoV-2 on reproductive
system.
There are several limitations in our study. First, the analysis in our study was limited
to one general hospital, but all cases had fulfilled the laboratory diagnosis of COVID-19.
Control group included patients who admitted to urology outpatient clinic and evaluated
for reproductive function had hormonal abnormalities. As another limitation, only
a single measurement of TT was available. Moreover, free and bioavailable testosterone
levels were not evaluated. Another limitation was neither semen analysis nor determination
of SARS-CoV-2 in semen was performed, which are more clear evidence for SARS-CoV-2
induced testis injury. Psychological stress is another factor effecting serum TT levels.
A current study evaluated psychological status of patients admitted with COVID-19
and presented that the predominant emotional state of patients for most days during
the stay or for almost all the days during the hospital stay was that of anxiety (92
%), remaining worried (96 %), and feeling isolated (90 %) (35). However, the authors
could not compare their results with that of existing literature because of limited
data on experiences of people with COVID-19. Several studies evaluating the impact
of stress on hormonal function in both human and animals confirmed that psychological
stress, especially chronic stress, inhibiting role in testosterone production (36).
Contrary to these studies presenting the decreasing effect of stress in serum testosterone
levels, in the literature, it has been shown psychological stress does not constantly
inhibit testosterone secretion (37). In addition to this contradictory studies, a
few studies exist which presented that testosterone concentration may be increased
at initial stages of acute stress (38, 39). Based on the aforementioned findings,
it is not possible to associate the reduction of serum TT levels in patients with
COVID-19 with their psychological stress in acute phase of the disease. However, even
if not the lack of the evaluation of the emotional status of patients and controls
is a limitation of the study.
Conclusion:
This study demonstrates COVID-19 is associated with decreased level of TT and increased
level of LH and prolactin. More serious COVID-19 causes more reduction in TT levels
and prolongs hospitalization period. In light of these findings, physicians may consider
to evaluate male patients with COVID-19 for concomitant androgen deficiency.