ArticlePDF AvailableLiterature Review

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


Abstract and Figures

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.
Content may be subject to copyright.
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
1. Chan JF-W, Yuan S, Kok K-H, To KK-W, Chu H, YangJ, et al. A
familial cluster of pneumonia associated with the 2019 novel
coronavirus indicating person-to-person transmission: a study of
a family cluster. Lancet. 2020;395:51423.
2. Li H, Liu S-M, Yu X-H, Tang S-L, Tang C-K. Coronavirus dis-
ease 2019 (COVID-19): current status and future perspectives. Int
J Antimicrob Agents. 2020;55:105951.
3. Guo Y-R, Cao Q-D, Hong Z-S, Tan Y-Y,Chen S-D, Jin H-J, et al.
The origin, transmission and clinical therapies on coronavirus dis-
ease 2019 (COVID-19) outbreak - an update on the status. Mil
Med Res. 2020;7:11.
4. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A
pneumonia outbreak associated with a new coronavirus of proba-
ble bat origin. Nature. 2020;579:2703.
5. Zheng J. SARS-CoV-2: an emerging coronavirus that causes a
global threat. Int J Biol Sci. 2020;16:167885.
6. Lai C-C, Liu YH, Wang C-Y, Wang Y-H, Hsueh S-C, Yen M-Y,
et al. Asymptomatic carrier state, acute respiratory disease, and
pneumonia due to severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2): facts and myths. J Microbiol Immunol Infect.
7. Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe
disease and death. BMJ. 2020;368:m1198.
8. Kandasamy M. Perspectives for the use of therapeutic Botulinum
toxin as a multifaceted candidate drug to attenuate COVID-19.
Med Drug Discov. 2020:100042.
9. Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations
and potential fecaloral transmission. Gastroenterology.
10. Li R, Yin T, Fang F, Li Q, Chen J, Wang Y, et al. Potential risks of
SARS-Cov-2 infection on reproductive health. Reprod BioMed
Online. 2020;41:8995.
11. Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular com-
plications in COVID-19. Am J Emerg Med. 2020;38:15047.
12. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al.
Nervous system involvement after infection with COVID-19 and
other coronaviruses. Brain Behav Immun. 2020;87:1822. https://
13. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al.
Pathological findings of COVID-19 associated with acute respi-
ratory distress syndrome. Lancet Respir Med. 2020;8:4202.
14. Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms
of coronavirus cell entry mediated by the viral spike protein.
Viruses. 2012;4:101133.
15. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T,
Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and
TMPRSS2 and is blocked by a clinically proven protease inhibi-
tor. Cell. 2020;181:271280.e8.
16. Vaarala MH, PorvariKS, Kellokumpu S, Kyllönen AP, VihkoPT.
Expression of transmembrane serine protease TMPRSS2 in mouse
and human tissues. J Pathol. 2001;193:13440.
17. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van
Goor H. Tissue distribution of ACE2 protein, the functional re-
ceptor for SARS coronavirus. A first step in understanding SARS
Reprod. Sci.
pathogenesis. J Pathol. 2004;203:6317.
18. Cao X. COVID-19: immunopathology and its implications for
therapy. Nat Rev Immunol. 2020;20:12.
19. Arbour N, Day R, Newcombe J, Talbot PJ. Neuroinvasion by
human respiratory coronaviruses. J Virol. 2000;74:891321.
20. Abobaker A, Raba AA. Does COVID-19 affect male fertility?
World J Urol. 2020:12.
21. Chen F, Lou D. Rising concern on damaged testis of COVID-19
patients. Urology. 2020;142:42.
22. Sepehrinezhad A, Shahbazi A, Negah SS. COVID-19 virus may
have neuroinvasive potential and cause neurological complica-
tions: a perspective review. J Neuro-Oncol. 2020;26:16. https://
23. Das G, Mukherjee N, Ghosh S. Neurological insights of COVID-
19 pandemic. ACS Chem Neurosci. 2020;11:12069. https://doi.
24. Li Y-C, Bai W-Z, Hashikawa T. The neuroinvasive potential of
SARS-CoV2may play a role in the respiratory failure of COVID-
19 patients. J Med Virol. 2020;92:5525.
25. Pascual-Goñi E, Fortea J, Martínez-Domeño A, Rabella N,
Tecame M, Gómez-Oliva C, et al. COVID-19-associated
ophthalmoparesis and hypothalamic involvement. Neurol
Neuroimmunol Neuroinflamm. 2020;7:e823.
26. Baig AM, Khaleeq A, Ali U, SyedaH. Evidence of the COVID-19
virus targeting the CNS: tissue distribution, hostvirus interaction,
and proposed neurotropic mechanisms. ACS Chem Neurosci.
27. Yu J. Endocrine disorders and the neurologicmanifestations. Ann
Pediatr Endocrinol Metab. 2014;19:18490.
28. Ranabir S, Reetu K. Stress and hormones. Indian J Endocrinol
Metab. 2011;15:1822.
29. Tsigos C, Kyrou I, Kassi E, Chrousos GP. Stress, endocrine phys-
iology and pathophysiology. In: Feingold KR, Anawalt B, Boyce
A, Chrousos G, de Herder WW, Dungan K, et al., editors.
Endotext. South Dartmouth:, Inc.; 2000.
30. Kandasamy M, Radhakrishnan RK, Poornimai Abirami GP,
Roshan SA, Yesudhas A, Balamuthu K, et al. Possible existence
of the hypothalamic-pituitary-hippocampal (HPH) axis: a recipro-
cal relationship between hippocampal specific neuroestradiol syn-
thesis andneuroblastosis in ageing brains withspecial reference to
menopause and neurocognitive disorders. Neurochem Res.
31. Pal R. COVID-19, hypothalamo-pituitary-adrenal axis and clini-
cal implications. Endocrine. 2020;68:12.
32. Oyola MG, Handa RJ. Hypothalamicpituitaryadrenal and hypo-
thalamicpituitarygonadal axes: sex differences in regulation of
stress responsivity. Stress. 2017;20:47694.
33. Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expres-
sion in testes: implications in coronavirus disease 2019 pathogen-
esis. Biol Reprod. 2020;103:44951.
34. Cardona Maya WD, Du Plessis SS, Velilla PA. SARS-CoV-2and
the testis: similarity with other viruses and routes of infection.
Reprod BioMed Online. 2020;40:7634.
35. Shen Q, Xiao X, Aierken A, Yue W, Wu X, Liao M, et al. The
ACE2 expression in Sertoli cells and germ cells may cause male
reproductive disorder after SARS-CoV-2 infection. J Cell Mol
Med. 2020;24:94727.
36. Stanley KE, Thomas E,Leaver M, Wells D. Coronavirusdisease-
19 and fertility: viral host entry protein expression in male and
female reproductive tissues. Fertil Steril. 2020;114:3343. https://
37. Yang M, Chen S, Huang B, Zhong J-M, Su H, Chen Y-J, et al.
Pathological findings in the testes of COVID-19 patients: clinical
implications. Eur Urol Focus. 2020;6:11249.
38. Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, et al. No evidence
of severe acute respiratory syndromecoronavirus 2 in semen of
males recovering from coronavirus disease 2019. Fertil Steril.
39. Wang S, Zhou X, Zhang T,Wang Z. The need for urogenital tract
monitoring in COVID-19. Nat Rev Urol. 2020;17:12. https://doi.
40. Vishvkarma R, Rajender S. Could SARS-CoV-2 affect male fer-
tility? Andrologia. 2020;52:e13712.
41. Ma L, Xie W, Li D, Shi L, Ye G,Mao Y, et al. Evaluation of sex-
related hormones and semen characteristics in reproductive-aged
male COVID-19 patients. J Med Virol. 2020.
42. Çayan S, Uğuz M, Saylam B, Akbay E. Effect of serum total
testosterone and its relationship with other laboratory parameters
on the prognosis of coronavirus disease 2019 (COVID-19) in
SARS-CoV-2 infected male patients: a cohort study. Aging
Male. 2020:111.
43. Karlberg J, Chong DSY, Lai WYY. Do men have a higher case
fatality rate of severe acute respiratory syndrome than womendo?
Am J Epidemiol. 2004;159:22931.
44. Jin J-M, Bai P, He W, Wu F, Liu X-F, Han D-M, et al. Gender
differences in patients with COVID-19: focus on severity and
mortality. Front Public Health. 2020;8.
45. Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz
DK, Perlman S. Sex-based differences in susceptibility to SARS-
CoV infection. J Immunol. 2017;198:404653.
46. Salonia A, Corona G, Giwercman A, Maggi M, Minhas S, Nappi
RE, et al. SARS-CoV-2, testosterone and frailty in males
(PROTEGGIMI): a multidimensional research project.
Andrology. 2020.
47. Wang Z, Xu X. scRNA-seq profiling of human testes reveals the
presence of the ACE2 receptor, a target for SARS-CoV-2 infec-
tion in spermatogonia, Leydig and Sertoli cells. Cells. 2020:9.
48. Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau
S, et al. Androgen regulationof the TMPRSS2 geneand the effect
of a SNP in an androgen response element. Mol Endocrinol.
49. Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True
LD, et al. The androgen-regulated protease TMPRSS2 activates a
proteolytic cascade involving components of the tumor microen-
vironment and promotes prostate cancer metastasis. Cancer
Discov. 2014;4:131025.
50. Chen Z, Mi L, Xu J, Yu J, Wang X, Jiang J, et al. Function of
HAb18G/CD147 in invasion of host cells by severe acute
Reprod. Sci.
respiratory syndrome coronavirus. J Infect Dis. 2005;191:75560.
51. Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment:
suggested effects of azithromycin and stem cell engagement. Stem
Cell Rev Rep. 2020;16:17.
52. López-Romero R, Nambo-Lucio M d J, Salcedo-Carrillo E,
Hernández-Cueto M d LÁ, Salcedo-Vargas M. The big challenge
of SARS-CoV-2 latency: testes as reservoir. Gac Med Mex.
53. Zhao J, Zhou G, Sun Y, Wang S, Yang J, Meng E, et al. Clinical
pathology and pathogenesis of severe acute respiratory syndrome.
Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2003;17:
54. Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ
distribution of severe acute respiratory syndrome (SARS) associ-
ated coronavirus (SARS-CoV) in SARS patients: implications for
pathogenesis and virus transmission pathways. J Pathol.
55. Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, et al. Multiple
organ infection and the pathogenesis of SARS. J Exp Med.
56. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a
complication of severe acute respiratory syndrome (SARS)1.
Biol Reprod. 2006;74:4106.
57. Olaniyan OT, Dare A, Okotie GE, Adetunji CO, Ibitoye BO,
Bamidele OJ, et al. Testis and blood-testis barrier in Covid-19
infestation: role of angiotensin-converting enzyme 2 in male in-
fertility. J Basic Clin Physiol Pharmacol. 2020;0.
58. SongC,WangY,LiW,HuB,ChenG,XiaP,etal.Absenceof
2019 novel coronavirus in semen and testes of COVID-19 pa-
tients. Biol Reprod. 2020;103:46.
59. Dittmayer C, Meinhardt J, Radbruch H, Radke J, Heppner BI,
Heppner FL, et al. Why misinterpretation of electron micrographs
in SARS-CoV-2-infected tissue goes viral. Lancet. 2020;396:e64
60. Goldsmith CS, Miller SE, Martines RB, Bullock HA, Zaki SR.
Electron microscopy of SARS-CoV-2: a challenging task. Lancet.
61. Kim J, Thomsen T, Sell N, Goldsmith AJ. Abdominal and testic-
ular pain: an atypical presentation of COVID-19. Am J Emerg
Med. 2020;38:1542.e13.
62. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest
D, Adams O, et al. Assessment of SARS-CoV-2 in human semen-
a cohort study. Fertil Steril. 2020;114:2338.
63. Özveri H, Eren MT, Kırışoğlu CE, Sarıgüzel N. Atypical presen-
tation of SARS-CoV-2 infection in male genitalia. Urol Case Rep.
64. La Marca A, Busani S, Donno V, Guaraldi G, Ligabue G, Girardis
M. Testicular pain as an unusual presentation of COVID-19: a
brief review of SARS-CoV-2 and the testis. Reprod BioMed
Online. 2020;41:9036.
65. Pozzilli P, Lenzi A. Testosterone, a key hormone in the context of
COVID-19 pandemic. Metabolism. 2020;108:154252. https://doi.
66. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-
19 infection: the perspectives on immune responses. Cell Death
Differ. 2020;27:14.
67. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of
COVID-19: immunity, inflammation and intervention. Nat Rev
Immunol. 2020;20:36374.
68. Aitken RJ, Roman SD. Antioxidant systems and oxidative stress
in the testes. Oxidative Med Cell Longev. 2008;1:1524.
69. Asadi N, Bahmani M, Kheradmand A, Rafieian-Kopaei M. The
impact of oxidative stress on testicular function and the role of
antioxidants in improving it: a review. J Clin Diagn Res.
70. Abd-Allah AR, Helal GK, Al-Yahya AA, Aleisa AM, Al-Rejaie
SS, Al-Bakheet SA. Pro-inflammatory and oxidative stress path-
ways which compromise sperm motility and survival may be al-
tered by L-carnitine. Oxidative Med Cell Longev. 2009;2:7381.
71. Youssef K, Abdelhak K. Male genital damage in COVID-19 pa-
tients: are available data relevant? Asian J Urol. 2020. https://doi.
72. Almasry SM, Hassan ZA, Elsaed WM, Elbastawisy YM.
Structural evaluation of the peritubular sheath of ratstestesafter
administration of ribavirin: a possible impact on the testicular
function. Int J Immunopathol Pharmacol. 2017;30:28296.
73. Narayana K, DSouza UJA, Narayan P, Kumar G. The antiviral
drug ribavirin reversibly affects the reproductive parameters in the
male Wistar rat. Folia Morphol (Warsz). 2005;64:6571.
74. Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-
CoV-2 infection upon male gonadal function: a single center-
based study. MedRxiv 2020:2020.03.21.20037267. https://doi.
75. Fassbender K, Schmidt R, Mössner R, Kischka U, Kühnen J,
Schwartz A, et al. Mood disorders and dysfunction of the
hypothalamic-pituitary-adrenal axis in multiple sclerosis: associa-
tion with cerebral inflammation. Arch Neurol. 1998;55:6672.
76. Lechan RM, Toni R. Functional anatomy of thehypothalamus and
pituitary. In: Feingold KR, Anawalt B, Boyce A, Chrousos G,
Dungan K, Grossman A, et al., editors. Endotext. South
Dartmouth:, Inc.; 2000.
77. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep
and circadian rhythms. Nature. 2005;437:125763. https://doi.
78. Guijarro A, Laviano A, Meguid MM. Hypothalamic integration of
immune function and metabolism. Prog Brain Res. 2006;153:
79. Daniel PM. Anatomy of the hypothalamus and pituitary gland. J
Clin Pathol Suppl (Assoc Clin Pathol). 1976;7:17.
80. Smith SM, Vale WW. The role of the hypothalamic-pituitary-
adrenal axis in neuroendocrine responses to stress. Dialogues
Clin Neurosci. 2006;8:38395.
81. Selvaraj K, Manickam N, Kumaran E, Thangadurai K, Elumalai
G, Sekar A, et al. Deterioration of neuroregenerative plasticity in
association with testicular atrophy and dysregulation of the
hypothalamic-pituitary-gonadal (HPG) axis in Huntingtonsdis-
ease: a putative role of the huntingtin gene in steroidogenesis. J
Steroid Biochem Mol Biol. 2020;197:105526.
82. Kliesch S, Schweifer B, Niklowitz P, Nieschlag E, Bergmann M.
The influence of LH and/or FSH on Leydig and Sertoli cell mor-
phology after testicular involution in the Djungarian hamster,
Phodopus sungorus, induced by hypophysectomy or short photo-
periods. Andrologia. 1991;23:99107.
83. Ramaswamy S, Weinbauer GF. Endocrine control of spermato-
genesis: role of FSH and LH/ testosterone. Spermatogenesis.
84. Plant TM. The hypothalamo-pituitary-gonadal axis. J Endocrinol.
Reprod. Sci.
85. Clavijo RI, Hsiao W. Update on male reproductive endocrinology.
Transl Androl Urol. 2018;7:S36772.
86. Viau V. Functional cross-talk between the hypothalamic-pituitary-
gonadal and -adrenal axes. J Neuroendocrinol. 2002;14:50613.
87. Acevedo-Rodriguez A, Kauffman AS, Cherrington BD, Borges
CS, Roepke TA, Laconi M. Emerging insights into hypothalamic-
pituitary-gonadal axis regulation and interaction with stress sig-
nalling. J Neuroendocrinol. 2018;30:e12590.
88. Julkunen I, Melén K, Nyqvist M, Pirhonen J, Sareneva T,
Matikainen S. Inflammatory responses in influenza A virus infec-
tion. Vaccine. 2000;19(Suppl 1):S327.
89. Mogensen TH, Paludan SR. Molecular pathways in virus-induced
cytokine production. Microbiol Mol Biol Rev. 2001;65:13150.
90. Malmgaard L. Induction and regulation of IFNs during viral in-
fections. J Interf Cytokine Res. 2004;24:43954.
91. Osuji FN, Onyenekwe CC, Ahaneku JE, Ukibe NR. The effects of
highly active antiretroviral therapy on the serum levels of pro-
inflammatory and anti-inflammatory cytokines in HIV infected
subjects. J Biomed Sci. 2018;25:88.
92. Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of
inflammation and infection. Front Immunol. 2018;9. https://doi.
93. Jaffer U, Wade RG, Gourlay T. Cytokines in the systemic inflam-
matory response syndrome: a review. HSR Proc Intensive Care
Cardiovasc Anesth. 2010;2:16175.
94. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease.
Int J Mol Sci. 2019;20.
95. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe
COVID-19: a meta-analysis. J Med Virol. 2020;92:22835.
96. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou
K, Antoniadou A, Antonakos N, et al. Complex immune dysreg-
ulation in COVID-19 patients with severe respiratory failure. Cell
Host Microbe. 2020;27:9921000.e3.
97. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiol-
ogy: a review. Clin Immunol. 2020;215:108427.
98. Zhang W, Zhao Y, Zhang F, Wang Q,Li T, Liu Z, et al. The use of
anti-inflammatory drugs in the treatment of people with severe
coronavirus disease 2019 (COVID-19): the perspectives of clini-
cal immunologists from China. Clin Immunol. 2020;214:108393.
99. Leszek J, Barreto GE, Gąsiorowski K, Koutsouraki E, Ávila-
Rodrigues M, Aliev G. Inflammatory mechanisms and oxidative
stress as key factors responsible for progression of neurodegener-
ation: role of brain innate immune system. CNS Neurol Disord
Drug Targets. 2016;15:32936.
100. Dandona P, Rosenberg MT. A practical guide to male
hypogonadism in the primary care setting. Int J Clin Pract.
101. Tremellen K, McPhee N, Pearce K, Benson S, Schedlowski M,
Engler H. Endotoxin-initiated inflammation reduces testosterone
production in men of reproductive age. Am J Physiol Endocrinol
Metab. 2018;314:E20613.
102. Fischer S, Ehlert U, Amiel CR. Hormones of the hypothalamic-
pituitary-gonadal (HPG) axis in maledepressive disorders - a sys-
tematic review and meta-analysis. Front Neuroendocrinol.
103. Mastorakos G, Pavlatou MG, Mizamtsidi M. The hypothalamic-
pituitary-adrenal and the hypothalamic-pituitary-gonadal axes in-
terplay. Pediatr Endocrinol Rev. 2006;3(Suppl 1):17281.
104. Whirledge S, Cidlowski JA. Glucocorticoids, stress, and fertility.
Minerva Endocrinol. 2010;35:10925.
105. Sansone A, Mollaioli D, Ciocca G, Limoncin E, Colonnello E,
Vena W, et al. Addressing male sexual and reproductive health in
the wake of COVID-19 outbreak. J Endocrinol Investig. 2020.
106. Dutta S, Sengupta P. SARS-CoV-2 and male infertility: possible
multifaceted pathology. Reprod Sci. 2020:14.
107. Mieusset R, Bujan L, Plantavid M, Grandjean H. Increased levels
of serum follicle-stimulating hormone and luteinizing hormone
associated with intrinsic testicular hyperthermia in oligospermic
infertile men. J Clin Endocrinol Metab. 1989;68:41925. https://
108. Lizneva D, Rahimova A, Kim S-M, Atabiekov I, Javaid S,
Alamoush B, et al. FSH beyond fertility. Front Endocrinol
(Lausanne). 2019;10:136.
109. Nedresky D, Singh G. Physiology, luteinizing hormone.
StatPearls, Treasure Island: StatPearls Publishing; 2020.
110. Levitan D, Moser SA, Goldstein DA, Kletzky OA, Lobo RA,
Massry SG. Disturbances in the hypothalamic-pituitary-gonadal
axis in male patients with acute renal failure. Am J Nephrol.
111. Holley JL. The hypothalamic-pituitary axis in men and women
with chronic kidney disease. Adv Chronic Kidney Dis. 2004;11:
112. Zacharias BT, Coelho JCU, Parolin MB, Matias JEF, de Freitas
ACT, de Godoy JL. Hypothalamic-pituitary-gonadal function in
men with liver cirrhosis before and after liver transplantation. Rev
Col Bras Cir. 2014;41:4215.
113. Neong SF, Billington EO, Congly SE. Sexual dysfunction and sex
hormone abnormalities in patients with cirrhosis: review of path-
ogenesis and management. Hepatology. 2019;69:268395.
114. Atwood CS, Meethal SV, Liu T, Wilson AC, Gallego M, Smith
MA, et al. Dysregulation of the hypothalamic-pituitary-gonadal
axis with menopause and andropause promotes neurodegenerative
senescence. J Neuropathol Exp Neurol. 2005;64:93103. https://
115. Meikle AW. The interrelationships between thyroid dysfunction
and hypogonadism in men and boys. Thyroid. 2004;14(Suppl 1):
PublishersNoteSpringer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
Reprod. Sci.
... This could result in a central hypothyroidism (Sandru et al., 2021), besides potential damage from the virus to the thyroid gland itself (Croce et al., 2021). COVID-19 injury of the hypothalamus is also proposed to lead to malfunction of the hypothalamic-pituitary-testicular axis (Ardestani Zadeh & Arab, 2021;Selvaraj et al., 2021) with possible effects on testicular function (Selvaraj et al., 2021). ...
... This could result in a central hypothyroidism (Sandru et al., 2021), besides potential damage from the virus to the thyroid gland itself (Croce et al., 2021). COVID-19 injury of the hypothalamus is also proposed to lead to malfunction of the hypothalamic-pituitary-testicular axis (Ardestani Zadeh & Arab, 2021;Selvaraj et al., 2021) with possible effects on testicular function (Selvaraj et al., 2021). ...
Full-text available
The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood–brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1–7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic–pituitary–adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.
... COVID-19-related complications include long-term disturbances occurring in nervous, cardio-respiratory, immune, endocrine and gastro-intestinal body systems (Ellul et al., 2020;Dennis et al., 2021;Selvaraj et al., 2021). Some post-COVID symptoms seem to be attributed to the isolated dysfunction of a single body system whereas other symptoms may stem from COVID-19-related dysfunction of multiple body systems. ...
... Possibly because of cortisol depletion in acute COVID-19, in post-acute COVID-19 condition, hypocortisolism linked with neurological disturbances, such as inability to concentrate and fatigue, were already reported (Ayat et al., 2021). Possible extraneural etiology of long-term post-COVID neurological symptoms may be at least partially supported by documented long-lasting dysfunctions of one or more organs in COVID-19 survivors (Dennis et al., 2021;Selvaraj et al., 2021). Another example of hypothetical causal link between the injury to extra-neural tissues caused by COVID-19 and neurological problems, might be associated with the cases of COVID-19-related pathophysiological processes in neuromuscular junction. ...
Full-text available
Theoretical considerations related to neurological post-COVID complications have become a serious issue in the COVID pandemic. We propose 3 theoretical hypotheses related to neurological post-COVID complications. First, pathophysiological processes responsible for long-term neurological complications caused by COVID-19 might have 2 phases: (1) Phase of acute Sars-CoV-2 infection linked with the pathogenesis responsible for the onset of COVID-19-related neurological complications and (2) the phase of post-acute Sars-CoV-2 infection linked with the pathogenesis responsible for long-lasting persistence of post-COVID neurological problems and/or exacerbation of another neurological pathologies. Second, post-COVID symptoms can be described and investigated from the perspective of dynamical system theory exploiting its fundamental concepts such as system parameters, attractors and criticality. Thirdly, neurofeedback may represent a promising therapy for neurological post-COVID complications. Based on the current knowledge related to neurofeedback and what is already known about neurological complications linked to acute COVID-19 and post-acute COVID-19 conditions, we propose that neurofeedback modalities, such as functional magnetic resonance-based neurofeedback, quantitative EEG-based neurofeedback, Othmer’s method of rewarding individual optimal EEG frequency and heart rate variability-based biofeedback, represent a potential therapy for improvement of post-COVID symptoms.
... Previous studies had already identified alterations in testicular endocrine function in 119 men of reproductive age infected with SARS-CoV-2, which had demonstrated an increase in LH levels and a decrease in the testosterone/LH ratio, probably reflecting an injury to Leydig cells, causing an early stage of transient hypogonadism (Ma et al., 2020;Drevet et al., 2021;Teixeira et al., 2021). In other reports, low testosterone levels were also identified in patients with COVID-19, but the samples showed alterations such as a reduction in Leydig cells, intense orchitis, and injury to the seminiferous tubules, which could explain the pathologic findings (Campos et al., 2021;Selvaraj et al., 2021;Duarte Neto et al., 2022). Hormonal regulation is more complex and dependent on sites and signals other than the gonads, which make up only a part of the hypothalamic-pituitary axis (Liu et al., 2018). ...
Full-text available
The ongoing COVID-19 pandemic represents an extra burden in the majority of public and private health systems worldwide beyond the most pessimistic expectations, driving an urgent rush to develop effective vaccines and effective medical treatments against the SARS-CoV-2 pandemic. The Nucleocapsid structural viral protein is remarkably immunogenic and hugely expressed during infection. High IgG antibodies against Nucleocapsid protein (N protein) levels were detected in the serum of COVID-19 patients, confirming its pivotal antigen role for a T lymphocyte response in a vaccine microenvironment. Currently, adverse events associated with immunizations have raised some degree of concern, irrespective of its huge benefits in dealing with disease severity and decreasing mortality and morbidity. This hitherto study evaluates histological changes in rats’ testes, epididymis, prostate, and seminal vesicles and analyzes hormone levels after solely N protein inoculation. Therefore, we exposed a group of Lewis rats to weekly injections of the recombinant N protein for 28 days, while a control group was inoculated with a buffer solution. The N group revealed a more significant number of spermatozoa. Spermatozoa in the seminiferous tubules were counted in twenty 400 × microscopy fields (mean of 9.2 vs. 4.6 in the control group; p < 0,01), but significantly lower testosterone levels (mean of 125.70 ng/dl vs. 309,00 ng/dl in the control group; p < 0,05) were found. No other histological and biochemical changes were displayed. Conclusively, these data suggest testicular hormonal imbalance mediated by the SARS-CoV-2 N protein that could be linked to reported post-COVID-19 syndrome hypogonadism. More relevant research might be performed to confirm this viral antigen’s deleterious mechanism in the human testicular microenvironment, particular in Leydig cell function.
... Host proteases such as transmembrane serine protease 2 (TMPRSS2) then cleaves the viral S protein causing a conformational change, allowing permanent fusion of the viral and host cell membranes, and thus infection. SARS-CoV-2 infection elicits a pro-inflammatory cytokine storm, resulting in multi-organ damage such as the lungs, heart, and brain, which are also identified as the main target of SARS-CoV-2 mediated pathogenesis (Selvaraj et al., 2021). The testes of men with COVID-19 are often not exempted from the cytokine storm. ...
Full-text available
The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male infertility has lately received significant attention. SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) in humans, has been shown to impose adverse effects on both the structural components and function of the testis, which potentially impact spermatogenesis. These adverse effects are partially explained by fever, systemic inflammation, oxidative stress, and an increased immune response leading to impaired blood-testis barrier. It has been well established that efficient cellular communication via gap junctions or functional channels is required for tissue homeostasis. Connexins and pannexins are two protein families that mediate autocrine and paracrine signaling between the cells and the extracellular environment. These channel-forming proteins have been shown to play a role in coordinating cellular communication in the testis and epididymis. Despite their role in maintaining a proper male reproductive milieu, their function is disrupted under pathological conditions. The involvement of these channels has been well documented in several physiological and pathological conditions and their designated function in infectious diseases. However, their role in COVID-19 and their meaningful contribution to male infertility remains to be elucidated. Therefore, this review highlights the multivariate pathophysiological mechanisms of SARS-CoV-2 involvement in male reproduction. It also aims to shed light on the role of connexin and pannexin channels in disease progression, emphasizing their unexplored role and regulation of SARS-CoV-2 pathophysiology. Finally, we hypothesize the possible involvement of connexins and pannexins in SARS-CoV-2 inducing male infertility to assist future research ideas targeting therapeutic approaches.
... Confirming previous observations on infection by SARS-CoV-1 (which is strictly linked to SARS-CoV-2), even the COVID-19 pandemic may influence endocrine organs such as the adrenals (4,5), thyroid (6)(7)(8)(9), testes (10)(11)(12), ovaries (13), pancreatic islets (14)(15)(16)(17), and pituitary (5,6,18,19). In lethal cases of COVID-19, autopsy studies revealed the virus within endocrine cells and explored alterations in endocrine organs (13,20). ...
Context Involvement of the pituitary gland in SARS-CoV-2 infection has been clinically suggested by pituitary hormone deficiency in severe COVID-19 cases, by altered serum ACTH levels in hospitalized patients, and by cases of pituitary apoplexy. However, the direct viral infection of the gland has not been investigated. Objectives To evaluate whether the SARS-CoV-2 genome and antigens could be present in pituitary glands of lethal cases of COVID-19, and to assess possible changes in the expression of immune-related and pituitary-specific genes. Methods SARS-CoV-2 genome and antigens were searched in the pituitary gland of 23 patients who died from COVID-19 and, as controls, in 12 subjects who died from trauma or sudden cardiac death. Real-time RT-PCR, in situ hybridization, immunohistochemistry and transmission electron microscopy were utilized. Levels of mRNA transcripts of immune-related and pituitary-specific genes were measured by the nCounter assay. Results The SARS-CoV-2 genome and antigens were detected in 14/23 (61%) pituitary glands of the COVID-19 group, not in controls. In SARS-CoV-2 positive pituitaries, the viral genome was consistently detected by PCR in the adeno- and the neurohypophysis. Immunohistochemistry, in situ hybridization and transmission electron microscopy confirmed the presence of SARS-CoV-2 in the pituitary. Activation of type I interferon signaling and enhanced levels of neutrophil and cytotoxic cell scores were found in virus-positive glands. mRNA transcripts of pituitary hormones and pituitary developmental/regulatory genes were suppressed in all COVID-19 cases irrespective of virus-positivity. Conclusion Our study supports the tropism of SARS-CoV-2 for human pituitary and encourage to explore pituitary dysfunction post-COVID-19.
... With regards to the hypothalamic-kisspeptin network in PCS, hypogonadism and altered gonadotropin hormones levels have been observed in COVID-19 [105,106]. However, whether HPG abnormalities and/or a direct effect on the gonads is the cause remains a matter for debate [107,108]. Additionally, the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in COVID-19 illness [109]. Interestingly, as the elimination of estrogen signaling on Kiss1 neurons leads to ovulatory failure [110], menopause has been described as an independent risk factor for female COVID-19 patients [111]. ...
Full-text available
Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments. Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.
... Notably, increased levels of ROS has been reported to suppress the circulating concentration of the male sex hormones leading to abnormal hypothalamic-pituitary-gonadal (HPG) axis and infertility related issues [50]. Thus, neutralization of abruptly increased levels of ROS by the implementation of pharmacological agents has been considered as a potent therapeutic regime for infertility in order to restore the testicular functions [51,52]. Earlier studies have indicated that the supplementation of antioxidants such as vitamin C, vitamin E and glutathione improves spermatogenesis and sperm quality [53,54]. ...
Full-text available
Background Botulinum toxin (BoNT) is a widely used therapeutic agent that blocks the excessive release of acetylcholine at the neuromuscular junction. Previously, repeated intracremasteric injections and slight overdose of BoNT have been reported to induce adverse effects in the testicular parameter of experimental rodents. However, a mild dose of BoNT is highly beneficial against skin ageing, neuromuscular deficits, overactive urinary bladder problems, testicular pain and erectile dysfunctions. Considering the facts, the possible therapeutic benefits of BoNT on the testis might be achieved at a very minimal dosage and via a distal route of action. Therefore, we revisited the effect of BoNT, but with a trace amount injected into the vastus lateralis of the thigh muscle, and analyzed histological parameters of the testis, levels of key antioxidants and sperm parameters in ageing experimental mice. Results Experimental animals injected with 1 U/kg bodyweight of BoNT showed enhanced spermatogenesis in association with increased activities of key antioxidants in the testis, leading to enhanced amount of the total sperm count and progressive motility. Conclusions This study signifies that a mild intramuscular dose of BoNT can be considered as a potent treatment strategy to manage and prevent male infertility.
Full-text available
İnsan endotelyal hücre spesifik molekül (ESM-1) olarak bilinen Endokan ilk kez 1996 yılında insan endotelyal hücrelerinden klonlanmıştır (1). 5. kromozomun uzun kolunda 3 ekson ve araya giren 2 introndan oluşan tek gen tarafından kodlanmaktadır. Primatlar ve memelilerde yüksek derecede korunmuş bir gene sahiptir. İlerleyen çalışmalar molekülün proteoglikan ailesinin üyesi olduğunu göstermiştir. Protein yapıdaki merkez kısım 165 amino asit içermektedir. 137. pozisyondaki serin amino asitine translasyon sonrası modifikasyon ile bağlı tek dermatan sülfat bulunmaktadır. N-terminal sisteinden zengin 110 amino asit içeren kısım ve C-terminal sisteinden fakir kısım olmak üzere iki temel bölümden meydan gelir (2). Endokan proteoglikan ailesinin diğer üyelerinden bazı özellikleri nedeni ile farklıdır. Fazla sayıda glikozaminoglikan içeren büyük moleküllü proteoglikanların aksine 20 kDa ağırlığında tek zincire sahiptir (1). Bunu yanı sıra, hücre dışı yatağın diğer elemanları gibi hücrelere yapısal destek olmanın ötesinde Endokan, temelde sekretuvar bir moleküldür (3).
Full-text available
Reactive oxygen species (ROS) are constantly formed in the cells throughout life, but there is an antioxidant defense system that interacts with them and reduces their effects. If the balance required by these two mechanisms is disturbed in favor of ROS, superoxide radicals accumulate in the cell and oxidative stress occurs. Free radicals damage the proteins, lipids and nucleic acids in the cell, disrupt the intracellular signaling pathways and cause many effects at the molecular level in the organism. Oxidative stress induced by free radicals can lead to the formation of many diseases such as neurological, immune system, endocrine system, cardiovascular system disorders and cancer. The effect of oxidative damage caused by free radicals is also great in the formation of aging and degenerative diseases related to aging
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
The serious coronavirus disease‐2019 (COVID‐19) was first reported in December 2019 in Wuhan, China. COVID‐19 is an infectious disease caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Angiotensin converting enzyme 2(ACE2) is the cellular receptor for SARS‐CoV‐2. Considering the critical roles of testicular cells for the transmission of genetic information between generations, we analyzed single‐cell RNA‐sequencing (scRNA‐seq) data of adult human testis. The mRNA expression of ACE2 was expressed in both germ cells and somatic cells. Moreover, the positive rate of ACE2 in testes of infertile men was higher than normal, which indicates that SARS‐CoV‐2 may cause reproductive disorders through pathway activated by ACE2 and the men with reproductive disorder may easily to be infected by SARS‐CoV‐2. The expression level of ACE2 was related to the age, and the mid‐aged with higher positive rate than young men testicular cells. Taken together, this research provides a biological background of the potential route for infection of SARS‐CoV‐2 and may enable rapid deciphering male‐related reproductive disorders induced by COVID‐19.
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.