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Testicular Atrophy and Hypothalamic Pathology in COVID-19: Possibility of the Incidence of Male Infertility and HPG Axis Abnormalities


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Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.
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Testicular Atrophy and Hypothalamic Pathology in COVID-19:
Possibility of the Incidence of Male Infertility and HPG
Axis Abnormalities
Kaviya Selvaraj
&Sowbarnika Ravichandran
&Sushmita Krishnan
&Risna Kanjirassery Radhakrishnan
Nivethitha Manickam
&Mahesh Kandasamy
Received: 12 July 2020 /Accepted: 16 December 2020
#Society for Reproductive Investigation 2021
Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of
the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis,
reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the
action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular
biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt
inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-
19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2
infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnor-
malities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology
resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors.
Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to second-
ary pathological complications in COVID-19 patients and survivors.
Keywords COVID-19 .SARS-CoV-2 .Testis .Hypothalamus .Inflammation .HPG axis
In the current uncertain life-changing scenario, the entire
world has been negatively impacted by the pandemic outbreak
of severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) [1,2]. Presently, persistent fever, chillness, cough,
pneumonia, and loss of smell and taste have been considered
as the emerging clinical symptoms of the SARS-CoV-2
infection-mediated coronavirus disease 2019 (COVID-19)
[35]. While a significant percentage of people with SARS-
CoV-2 infection are asymptomatic, clinical signs and patho-
genesis of COVID-19 appear to vary among infected individ-
uals depending upon the lifestyle, age, respiratory, metabolic,
renal, and cardiovascular conditions [68]. SARS-CoV-2
causes several life-threatening clinical complications includ-
ing acute respiratory distress syndrome (ARDS), cardiovascu-
lar failure, nervous system damage, gastrointestinal disorders,
and renal dysfunctions in a considerable number of COVID-
19 patients worldwide [913]. However, SARS-CoV-2-
induced clinical outcome and pathogenic events during and
post-recovery stages of COVID-19 are yet to be fully deter-
mined [8]. In general, the surface spike (S) viral proteins of
SARS-CoV-2 have an affinity towards angiotensin-
converting enzyme 2 (ACE2) and transmembrane serine pro-
tease 2 (TMPRSS2), through which it invades the host [14,
15]. Notably, ACE2 and TMPRSS2 are expressed by various
*Mahesh Kandasamy;
School of Life Sciences, Bharathidasan University,
Tiruchirappalli, Tamil Nadu 620024, India
Laboratory of Stem Cells and Neuroregeneration, Department of
Animal Science, School of Life Sciences, Bharathidasan University,
Tiruchirappalli, Tamil Nadu 620024, India
Faculty Recharge Programme, University Grants Commission
(UGC-FRP), New Delhi 110002, India
Reproductive Sciences
tissues and organs which have the potential risk of SARS-
CoV-2 infection leading tovarious pathological consequences
[1517]. While the lungs have been initially identified as the
primary pathogenic targets of SARS-CoV-2, an increasing
number of scientific evidence indicates comorbid clinical
symptoms and multi-organ defects including the pathology
of the testes and brain in COVID-19 patients [8,1821].
Notably, COVID-19 has been characterized by many neuro-
pathological signatures due to the neuroinvasive attribute of
SARS-CoV-2 [8,12,19,2225]. It has been reported that
SARS-CoV-2 can cross the bloodbrain barrier (BBB) and
infect the ACE2 expressing neurons and glial cells, thereby
leading to neuroinflammation and neuropathogenesis in the
brain regions including the hypothalamus that controls various
physiological functions like maintenance of the body temper-
ature and hormonal balance [8,12,17,25,26]. Dysregulation
of endocrine functions is an important clinical issue as it is
related to different disorders including hypothyroidism,
hypogonadism, anxiety, stress, and depression that are clearly
evident in COVID-19 cases [2730]. While the possible im-
pact of COVID-19 on the abnormal hypothalamic-pituitary-
adrenal (HPA) axis has been speculated [31], SARS-CoV-2-
mediated dysregulation of the hypothalamic-pituitary-gonadal
(HPG) axis remains obscure. The brain and testes are
endocrinologically linked by gonadotropins and testosterone
through the regulation of the HPG feedback loop [30,32].
While testes-derived circulating levels of sex steroid hor-
mones are important for the regulation of the HPG axis and
reproductive functions, COVID-19-associated testicular dys-
function, declined levels of testosterone and infertility require
an intense scientific focus.
Initially, the testes were thought to be the target of SARS-
CoV-2 due to the expression of the ACE2 in different cellular
compartments of the testes [21,3336]. However, evidence
for the presence of the viral particles in the testicular biopsies
and semen samples from COVID-19 patients is highly limited
[37,38]. Despite the unavailability of clear scientific proof for
the presence of SARS-CoV-2 in the testes and semen samples,
degeneration of seminiferous tubule, reduced number of
Leydig cells,and impaired spermatogenesis have been evident
in a significant number of COVID-19-positive cases [3739].
Besides, male subjects with COVID-19 have been reported to
exhibit a decreased level of testosterone and altered secretion
of the hypothalamus-mediated secretion of gonadotropins
such as luteinizing hormone (LH) and follicle-stimulating
hormone(FSH) in the pituitary [37,4042]. This article re-
visits the key reports on testicular abnormalities as well as
pathological signatures in the hypothalamus of COVID-19
patients. Further, the article supports a notion that COVID-
19 patients and survivors might be at risk of infertility due to
testicular atrophy, hypothalamic pathology, pituitary abnor-
malities, and disruption of sex hormone profile. Further inves-
tigations are required to monitor the reproductive health
parameters and HPG axis abnormalities related to secondary
pathological complications in the positive cases during and
after the recovery from COVID-19.
Testicular Dysfunction in COVID-19
The reports on the incidence of testicular pathology in
COVID-19 have increasingly been conclusive. It is clear that
men are more susceptible to SARS-CoV-2 infection than
women [43,44]. Abnormal levels of testosterone have been
identified as a key determinant for COVID-19-related patho-
genesis [45,46]. The transcriptome analysis studies of
human testicular tissues confirmed the prominent expression
of the ACE2 receptor and TMPRSS2 in spermatogonia, sper-
matids, Leydig cells, and Sertoli cells [36,47]. Moreover, the
expression of TMPRSS2 has been reported to be upregulated
by androgens in men [48,49]. Existing reports revealed that
the invasionof SARS-CoV-2 alsooccurs via CD14, a putative
marker of spermatogonial stem cells in the testes [50,51]. A
recent review by Lopez-Romero and colleagues posited that
testicular cells could be a possible target for SARS-CoV-2
infection due to the presence of its receptors in the testicular
cells [52]. However, the presence of SARS-CoV-2 in the tes-
tes and semen samples of COVID-19 patients remains a sub-
ject of debate. During the previous outbreak of SARS, Zhao
et al. indicated the presence of the virus in the testicular tissue
[53]. However, subsequent reports indicated the absence of
the viral particles in the testes, though orchitis and testicular
atrophy were common [5456]. Notably, Xu et al. reported a
pronounced leukocyte infiltration in the testes in association
with atrophy of the seminiferous epithelium in SARS-CoV-1-
affected patients [56]. Therefore, the possibilities for the
breakdown of the bloodtestis barrier (BTB) have been spec-
ulated in COVID-19 patients [57], which requires experimen-
tal validation. Recently, Yang and colleagues have provided
reverse transcription-polymerase chain reaction (RT-PCR)-
based evidence for the presence of SARS-CoV-2 in the testes
sample of a COVID-19 patient who was at the active repro-
ductive age [37]. However, a subsequent electron microscopic
examination revealed the absence of SARS-CoV-2 in testicu-
lar tissues of COVID-19 victims [37]. Further, a study by Pan
et al. reported the absence of SARS-CoV-2 in semen samples
collected from 34 male patients approximately 31 days after
being confirmed positive for COVID-19, while these patients
displayed viral orchitis, a clinical state of inflammation of
testicles at the time of diagnosis [38]. A similar study by
Song et al. further validated the absence of the virus in both
acute and recovery phases [58]. However, the aforementioned
studies havesome limitations including low sample size, mild
symptoms in the tested patients, and delayed processing of
samples. The examinations were done 3141 days after the
onset of disease, and it is possible that the virus lost its activity
Reprod. Sci.
or was eliminated by an immunological defence mechanism in
the testes as the clinical guidelines suggest an incubation pe-
riod of 14 days for SARS-CoV-2 [59,60]. Moreover, the
electron microscopic finding has been a subject of debate
due to possible misinterpretation of the data [59,60].
Therefore, it is not clear whether the virus could invade the
testicular tissue in the initial stage of SARS-CoV-2 infection
since most of the studies were done in the samples at a later
The post-mortem examinations of the human testes suggest
that SARS-CoV-2 infections lead to testicular inflammation,
edema, and degeneration of spermatogenic cells in association
with infiltration of CD3
and CD68
immune cells [56].
Recently, Kim et al. indicated that COVID-19 patients expe-
rienced testicular pain regardless of respiratory symptoms
[61]. A cohort study conducted by Holtman N et al. in the
semen samples of 18 men recovered from mild to moderate
COVID-19 revealed a low sperm count and poor sperm mo-
tility, though the viral particles were undetectable in the semen
[62]. As the above study was conducted 854 days after the
disappearance of COVID-19 symptoms, it is unclear whether
the viral RNA was present in the semen in the initial stage of
the infection. A case study by Özveri et al. indicated that a
male asymptomatic patient diagnosed positive for COVID-19
had swellingand severe pain in the left groin and testicle [63].
Another study by La Marca et al. reported that a diabetic
patient with severe bilateral testicular pain later developed
dyspnea and tested positive for COVID-19 [64]. However,
the reports on reduced circulating levels of testosterone in
COVID-19 cases clearly suggest the possibility of abnormal
spermatogenesis leading to infertility which might be largely
due to testicular inflammation [20,65].
Notably, SARS-CoV-2 infection has been reported to in-
duce the circulation of pro-inflammatory cytokines contribut-
ing to the pathogenic progression of COVID-19 [66,67]. In
general, pro-inflammatory cytokines and oxidative stress-
mediated free radicals cause degeneration in cellular compo-
nents of the testes [68,69]. The reduced levels of testosterone
and impaired spermatogenesis observed in COVID-19 have
also been related to persistent fever, elevated levels of pro-
inflammatory molecules and secondary autoimmune response
in the testes [6971]. Moreover, the treatment regime for
COVID-19 patients involves the use of anti-viral drugs like
Ribavirin which is known to induce oxidative stress, decrease
the levels of testosterone, and cause sperm abnormalities [72,
73]. Taken together, the occurrence of testicular abnormali-
ties, possibly at the level of reduced steroidogenesis and im-
paired spermatogenesis, can be considered as an important
pathogenic event in COVID-19 [74](Fig.1). In addition, re-
duced level of sex steroid hormones resulting from testicular
defects might be associated with abnormal regulation of the
HPG axis, while the SARS-CoV-2 infection appears to affect
the hypothalamus of the brain responsible for the sensing of
testes-derived sex steroid hormones. Therefore,understanding
the pathological impact of SARS-CoV-2 infection in the brain
affecting the hypothalamus might also be highly relevant with
reference to abnormal gonadotropin hormone levels.
Altered Levels of Gonadotropins in COVID-19
The hypothalamus is a crucial region of the brain that gener-
ates, integrates, and regulates various physiological processes
including the hormonal balance, blood pressure, basal homeo-
stasis, body temperature, circadian rhythm, sexual behavior,
and emotion [7578]. The hypothalamus is functionally
linked to the pituitary gland, adrenal gland, and gonads
through the circulating levels of stress hormones and gonadal
sex steroids [30,76,7981]. In general, the HPG axis is reg-
ulated by the release of gonadotropin-releasing hormone
(GnRH) from the hypothalamus in response to a decrease in
the circulating level of sex steroid hormones especially testos-
terone in the case of males. FSH and LH are produced in the
anterior pituitary by stimulation of the hypothalamus-derived
GnRH [30,31]. While FSH acts on the Sertoli cells, LH tar-
gets Leydig cells in the testes leading to the synthesis of tes-
tosterone responsible for spermatogenesis [82,83]. As a feed-
back loop, the circulating concentration of testosterone acts at
the hypothalamus to decrease the release of GnRH in order to
control the synthesis of FSH and LH in the pituitary [65,84,
85]. Local testosterone concentration in the testes is nearly
100 times greater than in the peripheral circulation, and it acts
on the Sertoli cells to promote spermatogenesis. In the phys-
iological state, the proper regulation of HPG axis is important
for reproductive function, whereas dysfunction of the HPG
axis has been reported to disrupt steroidogenesis and sper-
matogenesis in the testes, thereby leading to infertility and
psychological issues [81,86,87].
In theory, the neuropathogenic signals observed in the hy-
pothalamus could result ina decreased level of GnRH leading
to the suppression of the LH and FSH syntheses in the pitui-
tary. While the evidence for the altered levels of GnRH re-
mains to be established, a recent hormonal assessment-based
study by Ma et al. reported an increase in circulating levels of
LH in male subjects with COVID-19 contributing to abnormal
FSH/LH ratios [41]. Çayan S et al. indicated that the mean
values of LH and FSH concentrations rise in the circulation
along with the increase in the severity of COVID-19 [42].
During the previous epidemic outbreak of SARS-CoV in
2004, a transmission electron microscopy-based study by
Ding et al. revealed that the genome of SARS-CoV integrates
into the brain and pituitary gland [54]. A recent neuroimaging
finding by Pascual-Goñi et al. revealed a clear hyperintensity
signal indicating neurological lesion in the hypothalamus and
enlarged pituitary gland in a COVID-19-positive female pa-
tient [25]. The hypertrophy noticed in the pituitary gland of
Reprod. Sci.
COVID-19 could be a possible reason for the transient surge
of the gonadotropins [25]. Hence, it is too early tocharacterize
the basis for the circulating levels of gonadotropins in
COVID-19 cases with highly limited availability of scientific
data. While a growing body of evidence clearly indicates that
testicular pathology occurs due to COVID-19, it could lead to
disruption in the regulation of gonadotropins. The regulation
of the release of gonadotropins from the pituitary involves the
input from the hypothalamus. Therefore, hypothalamic pa-
thology seen in COVID-19 might also be linked with infertil-
ity in association with reduced testosterone resulting from
testicular atrophy.
Testicular Pathology: a Key Determinant
of Infertility and Dysfunction of HPG Axis
in COVID-19
In general, viral infections have been associated with fever
due to inflammatory responses and immunogenic reactions
[88]. Abnormal activation of immune cells upon viral infec-
tion can result in high levels of pro-inflammatory factors in-
cluding interferon-gamma (INF-γ), tumor necrosis factor
(TNF)-α, transforming growth factor (TGF)-β, and different
types of interleukins (ILs) [8991]. In addition, elevated levels
of C-reactive proteins (CRP) have been one of the clinical
hallmarks of viral infections [92]. Chronic activation of im-
mune cell-derived inflammatory cytokines contributes to
pathogenicity in different tissues and organs [93,94]. While
COVID-19 has been characterized by lymphopenia, the
spleen and lymph nodes of post-mortem tissues have been
characterized by the accumulation of ACE2-positive macro-
phages [8,9598]. In particular, the unregulatable activation
of immune cells like lymphocytes and macrophages that are
responsible for the surplus levels of inflammatory cytokines
could lead to oxidative stress and cell death in different organs
including the brain and testes [68,70,99]. Among the various
organs, the testes have been known to be highly vulnerable to
the enhanced inflammatory molecules and free radical-
mediated oxidative stress [68,70]. Notably, the pro-
inflammatory cytokines and oxidative stress are highly detri-
mental to the steroidogenesis and spermatogenesis in the tes-
tes [68,70]. In numerous pathogenic conditions, elevated
CRP and aberrant cytokine release such as INF-γhave been
known to induce defects in steroidogenesis and spermatogen-
esis in the testes. Taken together, given the massive cytokine
storm reported, the testes are at risk of structural and function-
al dysfunctions in subjects with COVID-19 regardless of the
direct infection of SARS-CoV-2 in the testes [74,100,101].
In healthy individuals, the hypothalamus of the brain
senses the circulating levels of testosterone and stimulates
the pituitary gland to secrete LH and FSH through GnRH as
a feedback mechanism, whereas in testicular pathogenesis,
reduction in the testosterone level might lead to the dysregu-
lation of the production of GnRH in the hypothalamus follow-
ed by the abnormal secretion of LH and FSH from the pitui-
tary [30,32,81,87,102]. The increased circulating levels of
LH and FSH reported in COVID-19 cases [41,42] could
indicate the transient activation of the gonadotropin-
producing cells due to early inflammatory responses (Fig. 1).
While testosterone, FSH, and LH are collectively involved in
the physiological regulation of the reproductive system, the
Fig. 1 Schematic representation of the regulation of HPG axis in healthy
and COVID-19 conditions. aRepresents the healthy human brain and
testes in association with the HPG axis. bRepresents a SARS-CoV-2
infected human brain and testes with neuroinflammation and dysregula-
tion of the HPG axis in association with reduced steroidogenesis and
spermatogenesis due to testicular inflammation and oxidative stress.
Reprod. Sci.
onset and progression of sexual disorders and infertility have
been attributed to testicular pathology and dysregulation of the
HPG axis [103,104]. Thus, it can be expected that COVID-19
survivors might be at a greater risk of developing sexual dis-
orders and infertility-related issues (Fig. 1).
Although the presence of SARS-CoV-2 in the testes remains
controversial, hypogonadism resulting from the inflammation
in the testes is increasingly evident [105,106]. Thus, a defect
in the steroidogenesis in the testes reflected by the reduced
level of testosterone may be the underlying basis for the ab-
normal levels of FSH and LH in patients with COVID-19. In
turn, low testosterone levels could lead to defects in spermato-
genesis, erectile dysfunction, and infertility inCOVID-19 [30,
107]. Therefore, understanding the impact of COVID-19 on
testicular pathology has become an important clinical respon-
sibility. FSH and LH have also been known to play roles in
non-reproductive functions, while increased levels of FSH
and LH have been reported to be the biomarkers for testicular
damage and some secondary pathologicalconsequences [108,
109]. The dysregulation of the HPG axis has been associated
with diseases like chronic kidney disease and liver cirrhosis
[110113]. Also, the incidence of disorders of HPG axis rang-
ing from hypothyroidism to neurodegenerative senescence
could be a likely consequence [102,114,115]. Therefore, a
detailed study of the endocrinological and reproductive pa-
rameters of COVID-19 patients has become inevitable.
Acknowledgments The authors acknowledge UGC-SAP and DST-FIST
for the infrastructure of the Department of Animal Science, Bharathidasan
University. Also, the authors gratefully acknowledge Prof. Erma Z.
Drobnis, Mrs. Raji Nirmal, and anonymous reviewers for their critical
reading and insightful suggestions on the manuscript.
Funding M.K. has been supported by the Faculty Recharge Programme,
University Grants Commission (UGC-FRP), New Delhi, India. M.K.
received a research grant (SERB-EEQ/2016/000639), an Early Career
Research Award (SERB-ECR/2016/000741) from the Science and
Engineering Research Board (SERB), government of India
and financial assistance from RUSA (Rashtriya Uchchatar Shiksha
Abhiyan) PHASE II, Biological Sciences. R.K.R. has been supported as
JRF from the project grant-ECR/2016/000741, SERB.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
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... The impact of COVID-19 on the male reproductive system is another topic that could garner significant community interest. Some studies portray that SARS-CoV-2 may negatively impact male fertility [4][5][6]. ...
... Gonadotropins and sex steroid hormones act to synchronize the brain and testes physiologically. SARS-CoV-2 has been found in the brain, and it has been hypothesized that the virus can infect brain cells because glial cells and neurons express ACE2, making them potential targets for SARS-CoV-2 infection [5,6]. Gonadotropin-releasing hormone (GnRH) is pulsatilely released from the hypothalamus by the hypothalamic-pituitary-gonadal axis (HPG). ...
Full-text available
COVID-19 has become a significant public health concern that has catastrophic consequences for society. Some preliminary evidence suggests that the male reproductive system may be an infection target for SARS-CoV-2. SARS-CoV-2 may be transmitted sexually, according to preliminary research. Testicular cells exhibit a high level of the angiotensin-converting enzyme 2 (ACE2) receptor, which enhances the entry of the SARS-CoV-2 into host cells. Some instances of COVID-19 have been documented to exhibit hypogonadism during the acute stage. Furthermore, systemic inflammatory reactions triggered by SARS-CoV-2 infection may cause oxidative stress (OS), which has been shown to have profoundly deleterious consequences on testicular functioning. This work gives a clear picture of how COVID-19 may affect male reproductive systems and calls attention to the many unanswered questions about the mechanisms by which this virus can be linked to men’s health and fertility.
... 8 Also, sex hormones are pretentious by COVID-19 due to dysregulation of the hypothalamic-pituitary-gonadal axis with subsequent reduction of circulating sex hormones. 9 One of the essential sex hormones is progesterone (P4), which has immunomodulatory effects in various viral infections and autoimmune diseases. 10 Therefore, this review tries to reveal the association between P4 and Covid-19. ...
Full-text available
Background : Coronavirus disease 2019 (COVID‐19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS‐CoV‐2). COVID‐19 is higher in men than women and sex hormones have immune‐modulator effects during different viral infections, including SARS‐CoV‐2 infection. One of the essential sex hormones is progesterone (P4). Aims : This review aimed to reveal the association between P4 and Covid‐19. Results and Discussion : The possible role of P4 in COVID‐19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti‐inflammatory cytokines, and inhibition release of pro‐inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti‐inflammatory Th2 with activation release of anti‐inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon‐gamma production that increased during SARS‐CoV‐2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS‐CoV‐2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ‐aminobutyric acid (GABA A ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID‐19 patients. Conclusion : Taken together, the anti‐inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID‐19.
... Pre-Testicular Effects: Impact of SARS-CoV-2 on Hypothalamus-Pituitary-Testicular AxisStudies related to the deteriorated impacts of SARS-CoV-2 on Hypothalamic region of brain suggest that the virus may have the capability to cross the Blood-Brain-Barrier (BBB) and infect the ACE2 rich cells thereby causing inflammation and pathogenesis in hypothalamic region which controls various physiological functions of the body including hormonal balance[54][55]. Male reproductive system which is highly under control of hypothalamus-pituitary-testicular (HPT) axis may get affected since changes in gonadotropic hormones (LH and FSH) release have been observed in COVID-19 positive male patients[56]. The reversible hypositis or direct hypothalamic damage that could have led to transient hypothalamic-pituitary dysfunction leading to adverse effect on release of gonadotropins were also been reported in studies on SARS-1 and SARS-2 ...
COVID-19 since its emergence in 2019 has become a global health challenge to deal with. Apart from other affected organs, the studies reporting presence of SARS-CoV-2 virus in male reproductive tract of Covid-19 patients has instigated a concern regarding its impact on male fertility. The high expression of Angiotensin-converting enzyme 2 (ACE2) receptor protein and TMPRSS2 in testis and other male accessory organs which facilitate the entry of virus in the human cells has increased the probability of viral invasion and its adversity in these organs. In this study we have systematical reviewed the current information available on different online portals to explore the possibility of direct and indirect effects if any of SARS-CoV-2 virus on male fertility organs following its clinical interpretations and consequences on male fertility outcome. The available literature showed disrupted hypothalamus-pituitary-testicular axis (hypogonadism), testicular orchitis and altered sperm parameters as major unavoidable risk of SARS-CoV-2 infection in male patients. However, with the limited clinical data, it is currently not appropriate to reach any conclusion and more follow-up studies on COVID-19 male survivors as well as in-depth studies for better understanding of molecular mechanism of SARS-CoV-2 virus inducing pathogenesis in male reproductive system affecting male reproductive health and fertility outcome are need to be conducted.
... It was found that there is a relationship between varicocele and immune markers, where the marks displayed a important rise in the level of cytokines 6 and 10 between varicose vein groups when compared with control groups [26], [27]. ...
Full-text available
Infertile males were tested for the presence of interleukin 6 and 10, as well as for the presence of lipid peroxidation in their sperm. A total of 75 men with varicoceles and 25 fertile men served as controls, with sperm samples collected via masturbation. Malondialdehyde (MDA) production in the sperm membrane was used to assess the degree of lipid peroxidation in the membrane. Statistics were used to examine the association between the quantities of interleukin-6 (IL-6) and interleukin-10 (IL-10) in plasma of seminal and lipid peroxidation levels of sperm membranes. There existed a statistically significant difference in the concentration of IL-6 in the seminal plasma of unfertile males and fertile men (p < 0.05) between the two groups. On the other hand, the concentration of interleukin-10 (IL-10) in the seminal plasma of infertile men was considerably greater than that of fertile men (p < 0.05), and the degree of lipid peroxidation in the semen of infertile men was significantly higher than that of fertile men (p < 0.05). in seminal plasma the levels of IL-6 and membrane lipid peroxidation procces in the spermatozoa were found to be positively related to each other (p < 0.05), while IL-10 levels in seminal plasma and lipid peroxidation membrane in sperm were found to be positively correlated with each other (p < 0.05). It seems that there is a potential link between plasma interleukin-10 and 6 and ranks of spermatozoa and peroxidation of fat in the sperm membrane based on these findings. It may explain the encouragement species reactive formed by sperm of males and leukocytes, which is stimulated by great ranks of IL-6. Moreover, IL-10 is categorised by chemoattractant action of both T cells and basophils, as well as by the use of a proangiogenic effect on vascular smooth muscle cells. IL-10 is a cytokine that shows a key character in a variety of inflammatory disorders.
... The male reproductive tract and testis may experience histological or functional alterations as a result of the SARS-CoV-2 infection, which will have an adverse effect on male fertility 33,179,180 . Men who have SARS-CoV-2 may have sperm damage; however, it has been discovered that hPM-SCs can mitigate this damage, encourage changes in sperm parameters, and boost testosterone levels, testicular size, and other factors. ...
Full-text available
The 2019 novel coronavirus disease (COVID-19) has lasted for over 3 years and has seriously affected the regular life trajectory of human beings. The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has caused non-negligible harm to people's respiratory systems and multiple organs. Although the pathogenesis of COVID-19 has been fully elucidated, there is still a lack of effective and specific treatment for COVID-19. Mesenchymal stem cells (MSCs) or MSC-derived extracellular vesicles (MSC-EVs) by far have become the most promising candidates in preclinical studies and clinical trials, and MSC-related therapies have shown their potential to treat severe COVID-19. The multidirectional differentiation potential and immunomodulatory function of MSCs have allowed the cells to exert multiple cellular and molecular actions on different immune cells and organs. It is critical to understand the therapeutic roles of MSCs before entering the clinics for COVID-19 and other diseases. This review summarizes the recent progress of particular mechanisms underlying the immunomodulatory and tissue regenerative effects of MSCs toward COVID-19. We focused on discussing the functional roles of MSC-mediated effects on immune cell responses, cell survival, and organ regeneration. Besides, the novel discoveries and recent findings of MSC clinical application in patients with COVID-19 were highlighted. This will provide an overview of the current research on the rapid development of MSC-based therapies not only for COVID-19 but also for other immune-mediated/immune-dysregulating diseases.
... Of note, thrombosis, cytokine storm, and hyperinflammation, SARS-CoV-2 infection may impair the HPG axis 35,36 . This may extend for a period and cause ED and male infertility. ...
Full-text available
Patients with coronavirus disease 2019 (COVID-19) were shown to have reduced serum testosterone levels compared to healthy individuals. Low testosterone levels are linked with the development of erectile dysfunction (ED). In this case-controlled study, 20 healthy controls and 39 patients with ED 3 months after recovering from mild-to-moderate COVID-19 pneumonia were studied. The patients ranged in age from 31 to 47 years. To identify early and late COVID-19 infections, real-time polymerase-chain reaction (RT-PCR) and COVID-19 antibody testing were done. The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), free testosterone (FT), free androgenic index (FAI), and sex hormone-binding globulin (SHBG) were measured. The sexual health inventory for patients (SHIM) score was used to measure the erectile function of the patients and controls. When compared to the controls, the TT serum level in long COVID-19 (LC) patients with ED was low (p = 0.01). In contrast to controls, FT and FAI were both lower in LC patients with ED. (p = 0.001). FSH serum levels did not significantly differ (p = 0.07), but in ED patients, LH serum levels were elevated. SHIM scores were associated with low TT (p = 0.30), FT (p = 0.09), and high LH (p = 0.76) in LC patients with ED. Male patients with decreased serum levels of LH and testosterone may have hypothalamic-pituitary–gonadal axis dysfunction, which could lead to the development of LC-induced ED. Therefore, an in-depth research is necessary to confirm the causal link between COVID-19 and ED in LC patients.
... Higher concentrations of LH and FSH reflect testicular damage and other pathological outcomes [144]. Dysregulation of the HPG axis could result in not only hypothyroidism but also neurodegenerative senescence, liver cirrhosis, and chronic kidney disease [145]. The multiple possible mechanisms by which SARS-CoV-2 affects spermatogenesis are as follows: direct damage to testicular tissue or sperm; exaggeration of immune response, OS, and apoptosis mediated by SARS-CoV-2 infection; dysregulation of hormone levels. ...
Full-text available
Purpose: The coronavirus 2019 (COVID-19) pandemic-caused by a new type of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-has posed severe impacts on public health worldwide and has resulted in a total of > 6 million deaths. Notably, male patients developed more complications and had mortality rates ~ 77% higher than those of female patients. The extensive expression of the SARS-CoV-2 receptor and related proteins in the male reproductive tract and the association of serum testosterone levels with viral entry and infection have brought attention to COVID-19's effects on male fertility. Methods: The peer-reviewed articles and reviews were obtained by searching for the keywords SARS-CoV-2, COVID-19, endocrine, spermatogenesis, epididymis, prostate, and vaccine in the databases of PubMed, Web of Science and Google Scholar from 2020-2022. Results: This review summarizes the effects of COVID-19 on the male reproductive system and investigates the impact of various types of SARS-CoV-2 vaccines on male reproductive health. We also present the underlying mechanisms by which SARS-CoV-2 affects male reproduction and discuss the potentially harmful effects of asymptomatic infections, as well as the long-term impact of COVID-19 on male reproductive health. Conclusion: COVID-19 disrupted the HPG axis, which had negative impacts on spermatogenesis and the epididymis, albeit further investigations need to be performed. The development of vaccines against various SARS-CoV-2 variations is important to lower infection rates and long-term COVID risks.
... Injured Sertoli cells lose their ability to nourish developing sperm cells, eventually disrupting spermatogenesis [74]. The damage to Leydig cells also dysregulates testosterone production [75], which could explain the decreased ratio of testosterone to LH and FSH to LH in COVID-19 male patients, as such disruption pattern is highly associated with Leydig cells dysfunction and hypogonadism [76][77][78]. ...
Full-text available
The respiratory system was primarily considered the only organ affected by Coronavirus disease 2019 (COVID-19). As the pandemic continues, there is an increasing concern from the scientific community about the future effects of the virus on male and female reproductive organs, infertility, and, most significantly, its impact on the future generation. The general presumption is that if the primary clinical symptoms of COVID-19 are not controlled, we will face several challenges, including compromised infertility, infection-exposed cryopreserved germ cells or embryos, and health complications in future generations, likely connected to the COVID-19 infections of parents and ancestors. In this review article, we dedicatedly studied severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) virology, its receptors, and the effect of the virus to induce the activation of inflammasome as the main arm of the innate immune response. Among inflammasomes, nucleotide oligomerization domain-like receptor protein, pyrin domain containing 3 (NLRP3) inflammasome pathway activation is partly responsible for the inflicted damages in both COVID-19 infection and some reproductive disorders, so the main focus of the discussion is on NLRP3 inflammasome in the pathogenesis of COVID-19 infection alongside in the reproductive biology. In addition, the potential effects of the virus on male and female gonad functions were discussed, and we further explored the potential natural and pharmacological therapeutic approaches for comorbidity via NLRP3 inflammasome neutralization to develop a hypothesis for averting the long-term repercussions of COVID-19. Since activation of the NLRP3 inflammasome pathway contributes to the damage caused by COVID-19 infection and some reproductive disorders, NLRP3 inflammasome inhibitors have a great potential to be considered candidates for alleviating the pathological effects of the COVID-19 infection on the germ cells and reproductive tissues. This would impede the subsequent massive wave of infertility that may threaten the patients.
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Background Although COVID-19 infection has dropped across the world and SARS-CoV-2 vaccines have been developed, global concerns remain about the disease’s long-term health consequences. The purpose of this research was to review the consequences of SARS-CoV-2 on male health, particularly the reproductive system and the pathogenic mechanisms affecting male infertility. Improving knowledge on these issues may help in considering to which extent some of the remaining concerns should be addressed. Results The primary target of this disease is the pulmonary system, but reproductive organs may be targeted by the virus. To enter host cells, the virus utilizes both ACE2 and TMPRSS2, which are differentially expressed in the spermatogonial stem, Leydig, and Sertoli cells, thereby providing possible testicular vulnerability. COVID-19-related stress and psychological distress may also affect aspects of male reproductive health. Conclusions Since some pathological effects of COVID-19 infection and dysregulations are linked to infertility, more attention is needed to determine whether such dysregulations regress following infection decline.
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Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), jeopardizes male fertility because of the vulnerability of the male reproductive system, especially the testes. This study evaluates the effects of the virus on testicular function and examines the potential role of antioxidants in mitigating the damage caused by oxidative stress (OS). A comprehensive PubMed search examined exocrine and endocrine testicular function alteration, the interplay between OS and COVID-19-induced defects, and the potential benefit of antioxidants. Although the virus is rarely directly detectable in sperm and testicular tissue, semen quality and hormonal balance are affected in patients, with some changes persisting throughout a spermatogenesis cycle. Testicular pathology in deceased patients shows defects in spermatogenesis, vascular changes, and inflammation. Acute primary hypogonadism is observed mainly in severely infected cases. Elevated OS and sperm DNA fragmentation markers suggest redox imbalance as a possible mechanism behind the fertility changes. COVID-19 vaccines appear to be safe for male fertility, but the efficacy of antioxidants to improve sperm quality after infection remains unproven due to limited research. Given the limited and inconclusive evidence, careful evaluation of men recovering from COVID-19 seeking fertility improvement is strongly recommended.
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Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli.
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Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes COVID-19 infections penetrates body cells by binding to angiotensin-converting enzyme-2 (ACE2) receptors. Evidence shows that SARS-CoV-2 can also affect the urogenital tract. Hence, it should be given serious attention when treating COVID-19-infected male patients of reproductive age group. Other viruses like HIV, mumps, papilloma and Epstein-Barr can induce viral orchitis, germ cell apoptosis, inflammation and germ cell destruction with attending infertility and tumors. The blood-testis barrier (BTB) and blood-epididymis barrier (BEB) are essential physical barricades in the male reproductive tract located between the blood vessel and seminiferous tubules in the testes. Despite the significant role of these barriers in male reproductive function, studies have shown that a wide range of viruses can still penetrate the barriers and induce testicular dysfunctions. Therefore, this mini-review highlights the role of ACE2 receptors in promoting SARS-CoV-2-induced blood-testis/epididymal barrier infiltration and testicular dysfunction.
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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/ml 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.
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During novel coronavirus 2019 (COVID-19) pandemic, patients usually present with several reports showing symptoms of severe systemic or respiratory illness and, although rare, some genital complaints such as scrotal discomfort can be seen. In the majority of patients, however, genital complaints seem not to be the initial or sole symptoms. In this article, we report an unusual presentation of a male case with severe external genital pain which was suspected to be the first clinical sign of COVID-19.
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PurposeThe COVID-19 pandemic, caused by the SARS-CoV-2, represents an unprecedented challenge for healthcare. COVID-19 features a state of hyperinflammation resulting in a “cytokine storm”, which leads to severe complications, such as the development of micro-thrombosis and disseminated intravascular coagulation (DIC). Despite isolation measures, the number of affected patients is growing daily: as of June 12th, over 7.5 million cases have been confirmed worldwide, with more than 420,000 global deaths. Over 3.5 million patients have recovered from COVID-19; although this number is increasing by the day, great attention should be directed towards the possible long-term outcomes of the disease. Despite being a trivial matter for patients in intensive care units (ICUs), erectile dysfunction (ED) is a likely consequence of COVID-19 for survivors, and considering the high transmissibility of the infection and the higher contagion rates among elderly men, a worrying phenomenon for a large part of affected patients. MethodsA literature research on the possible mechanisms involved in the development of ED in COVID-19 survivors was performed. ResultsEndothelial dysfunction, subclinical hypogonadism, psychological distress and impaired pulmonary hemodynamics all contribute to the potential onset of ED. Additionally, COVID-19 might exacerbate cardiovascular conditions; therefore, further increasing the risk of ED. Testicular function in COVID-19 patients requires careful investigation for the unclear association with testosterone deficiency and the possible consequences for reproductive health. Treatment with phosphodiesterase-5 (PDE5) inhibitors might be beneficial for both COVID-19 and ED.ConclusionCOVID-19 survivors might develop sexual and reproductive health issues. Andrological assessment and tailored treatments should be considered in the follow-up.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) has been declared a pandemic by the World Health Organization (WHO) on 11th March 2020. Bulk of research on this virus are carried out to unveil its multivariate pathology. Surprisingly, men are reportedly more vulnerable to COVID-19 even with higher fatality rate compared to women. Thus, it is crucial to determine whether SARS-CoV-2 infection can even affect male fertility as an immediate or long-term consequence of the disease. Among the discrete data available, an important finding is that angiotensin converting enzymes 2 (ACE2) receptor, that aids the SARS-CoV-2 entry into host cells, is profoundly expressed in testicular cells. In addition, the endogenous androgen milieu and its receptors are associated with ACE2 activation reflecting that enhanced testosterone levels may trigger the pathogenesis of COVID-19. In contrary, hypogonadism has also been reported in the acute phase of some COVID-19 cases. Moreover, SARS-CoV-2 infection-induced uncontrolled inflammatory responses may lead to systemic oxidative stress (OS), whose severe disruptive effects on testicular functions are well-documented. This article aims to precisely present the possible impact of COVID-19 on male reproductive functions, and to highlight the speculations that need in-depth research for the exact underlying mechanisms how COVID-19 is associated with men’s health and fertility.
In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.
Research Question Can SARS-CoV-2 induce testis damage and dysfunction? Design Description of the case of a young man presenting with heavy testicular pain as the first symptom of COVID-19. A review of the literature is also presented Results SARS-CoV-2 may enter into the host cell by binding to ACE2. This receptor seems to be widely expressed in different testicular cell types making possible the occurrence of orchitis in male COVID-19 patients. From a review of the literature, it seems that there is no evidence at this moment of sexual transmission of SARS-CoV-2, however the possibility of the virus induced testis damage and dysfunction could not be excluded. Conclusions Further studies are necessary on the pathological effect of SARS-CoV-2 in male reproductive system and to insure a proper andrological follow-up to male patients.
In the past several months, the outbreak of SARS‐CoV‐2‐associated infection (coronavirus disease 2019, COVID‐19) developed rapidly and has turned into a global pandemic. Although SARS‐CoV‐2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. Great concern was raised about whether COVID‐19 may affect male reproductive functions. In this study, we collected semen specimens from twelve male COVID‐19 patients for virus detection and semen characteristics analysis. No SARS‐CoV‐2 was found in semen specimens. 8 out of 12 patients had normal semen quality. We also compared the sex‐related hormone levels between 119 reproductive‐aged men with SARS‐CoV‐2 infection and 273 age‐matched control men. A higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID‐19 group. Multiple regression analysis indicated that serum T:LH ratio was negatively associated with white blood cell counts (WBC) and c‐reactive protein (CRP) level in COVID‐19 patients. It's the first report about semen assessment and sex‐hormone evaluation in reproductive‐aged male COVID‐19 patients. Although further study is needed to clarify the reasons and underlying mechanisms, our study presents an abnormal sex hormone secretion among COVID‐19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow‐up. This article is protected by copyright. All rights reserved.