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REVIEW
Testicular Atrophy and Hypothalamic Pathology in COVID-19:
Possibility of the Incidence of Male Infertility and HPG
Axis Abnormalities
Kaviya Selvaraj
1,2
&Sowbarnika Ravichandran
1,2
&Sushmita Krishnan
1
&Risna Kanjirassery Radhakrishnan
2
&
Nivethitha Manickam
2
&Mahesh Kandasamy
1,2,3
Received: 12 July 2020 /Accepted: 16 December 2020
#Society for Reproductive Investigation 2021
Abstract
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
Introduction
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)
[3–5]. 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 [6–8]. 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 [9–13]. 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
pkmahesh5@gmail.com; mahesh.kandasamy@bdu.ac.in
1
School of Life Sciences, Bharathidasan University,
Tiruchirappalli, Tamil Nadu 620024, India
2
Laboratory of Stem Cells and Neuroregeneration, Department of
Animal Science, School of Life Sciences, Bharathidasan University,
Tiruchirappalli, Tamil Nadu 620024, India
3
Faculty Recharge Programme, University Grants Commission
(UGC-FRP), New Delhi 110002, India
Reproductive Sciences
https://doi.org/10.1007/s43032-020-00441-x
tissues and organs which have the potential risk of SARS-
CoV-2 infection leading tovarious pathological consequences
[15–17]. 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 [8,18–21].
Notably, COVID-19 has been characterized by many neuro-
pathological signatures due to the neuroinvasive attribute of
SARS-CoV-2 [8,12,19,22–25]. It has been reported that
SARS-CoV-2 can cross the blood–brain 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 [27–30]. 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 [21,33–36]. 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 [37–39].
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 [37,40–42]. 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 [54–56]. 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 blood–testis 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 31–41 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
stage.
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 8–54 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 [69–71]. 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 [75–78]. The hypothalamus is functionally
linked to the pituitary gland, adrenal gland, and gonads
through the circulating levels of stress hormones and gonadal
sex steroids [30,76,79–81]. 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) [89–91]. 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 [8,95–98]. 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).
Conclusion
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
[110–113]. 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
interest.
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