JBRA Assist. Reprod. 2020;24(3):347-350
REVIEW ARTICLE
doi: 10.5935/1518-0557.20200047
1Department of Surgery, Division of Urology, Universidade Federal de São Paulo, São Paulo, Brazil
2Department of Health Sciences, School of Medicine, University of Caxias do Sul, Caxias do Sul, RS, Brazil
3Department of Reproductive Medicine, Mater Prime, São Paulo, Brazil
4Discipline of Human Reproduction, Institute of Biological Sciences and Health, Pontifical Catholic University of Minas Gerais, Brazil
ABSTRACT
Critical challenges for the public and private health, research, and medical
communities have been posed by the COVID-19 outbreak. Some of these challenges
are related to the possible adverse effects of SARS-CoV-2 on male reproductive
health, and whether other potential modes of transmission may occur, such as
sexual transmission. Moreover, concerns have been raised in terms of whether the
COVID-19 outbreak may have an impact on fertility worldwide. In this study, we
will discuss the origins of SARS-CoV-2. We will further describe its mechanism
of action, diagnosis, symptoms, and potential effects on the male reproductive
system.
Keywords: Semen, Covid-19, SARS-COV-2, male reproductive
Introduction
As of May 16, 2020, 4,434,653 confirmed cases and 302,169 deaths due to the novel
coronavirus disease 2019 (COVID-19) - which is caused by the new, severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) - have been reported worldwide (WHO,
2020a). Although COVID-19 was first identified as a respiratory disease, it is now
considered a systemic pathology, as it may affect different systems (Pan et al., 2020). New
challenges are now emerging concerning the disease, such as associated reproductive
implications and the consequences of assisted and natural conceptions in the
presence of acute COVID-19 infection and following patient recovery (Eisenberg 2020).
In the last 20 years, there were two previous pandemics related to coronavirus,
including the severe acute respiratory syndrome (SARS; 2002 and 2003) and the Middle
East respiratory syndrome (MERS; 2012), which did not reach the number of cases and
deaths associated with COVID-19. However, these previous pandemics have accelerated
our understanding of the epidemiology and pathogenesis of SARS-CoV-2 (Jin et al., 2020), and an
unprecedented number of research studies related to this disease have emerged.
Further, over 500 clinical trials have been registered among different national and
international clinical trial registry sites as of April 21, 2020, which aim to
evaluate different possible therapeutic options (Thorlund et al., 2020). Nevertheless, until now, no
specific and effective therapeutic strategies have been available to decrease the
fatality rates of COVID-19, and it seems that quarantine, isolation, and social
distancing remain the best strategies to deal with this novel pandemic (Hick &
Biddinger, 2020). Thus, critical challenges for the public and private health,
research, and medical communities have been posed by the COVID-19 outbreak (Fauci et al., 2020). Some of
these challenges are related to the possible adverse effects of SARS-CoV-2 on male
reproductive health, and whether other potential modes of transmission may occur,
such as sexual transmission. Moreover, concerns have been raised in terms of whether
the COVID-19 outbreak may have an impact on fertility worldwide (Cardona Maya et al., 2020).
In this study, we will discuss the origins of SARS-CoV-2. We will further describe
its mechanism of action, diagnosis, symptoms, and potential effects on the male
reproductive system.
SARS-CoV-2 history and origin
On December 31, 2019, Chinese health authorities announced dozens of pneumonia
infections of unknown etiology in Wuhan city (Hubei province). The infectious agent
was identified on 7 January 2020, and was classified as a novel coronavirus
(2019-nCoV)(Abduljalil & Abduljalil,
2020). On January 30, 2020, the World Health Organization (WHO) decreed a
public health emergency of international importance (Souza et al., 2020). Thereafter, on February 11, 2020,
the WHO announced that this novel coronavirus pneumonia was classified as
coronavirus disease-2019 (COVID-19)(WHO, 2020b). Due to its similarity with the
causative agent, SARS, the novel coronavirus was named SARS-CoV-2 by the
International Committee on Taxonomy of Viruses (Abduljalil & Abduljalil, 2020).
Given the global involvement of COVID-19, the WHO declared a pandemic on March 11,
2020 (Souza et al., 2020).
SARS-CoV-2 is the seventh identified member of the coronavirus family to affect
humans, and it is the third coronavirus to emerge in the human population in the
past two decades. Many details related to its origin and its ability to spread among
humans remain unknown (Munster et
al., 2020). Coronaviruses are a large family of enveloped,
single-stranded RNA viruses known to infect not only humans, but also other mammals
and birds, leading to respiratory, hepatic, gastrointestinal, and neurologic
diseases (Mungroo et al.,
2020; Zhu et al.,
2020). A genome-wide phylogenetic analysis indicated that SARS-CoV-2
shares 79.5% and 50% sequence identity with SARS-CoV and MERS-CoV, respectively
(Jin et al., 2020).
Although believed to originate from bats, it has been speculated that other animals,
such as pangolins and snakes, served as intermediate hosts, allowing the spillover
of SARS-CoV-2 as a distinct human virus (Abduljalil
& Abduljalil, 2020). However, phylogenetic analyses of the virus and
its closely related reference genomes indicate that the origin of the virus has yet
to be determined (Zhou et al.,
2020).
SARS-CoV-2 mechanism of action
SARS-CoV-2 has four key structural proteins, namely nucleocapsid (N), spike (S),
small membrane (SM), and membrane (M) proteins. The S protein is required for the
virus to fuse to the host cell through the receptor-binding-domain (Monteleone et al., 2020). The
main path for SARS-CoV-2 entry into the cell is via the attachment of the S protein
to the angiotensin-converting enzyme 2 (ACE2) that can be identified in type II
alveolar cells, myocardial cells, proximal tubule cells of the kidney, ileum and
esophagus epithelial cells, and bladder urothelial cells (Zhou et al., 2020). ACE2 can also be
identified in the human testis, as it is highly expressed in Leydig and seminiferous
tubules cells (Fan et al., 2020). Thus, it is hypothesized that
SARS-CoV-2 may bind to ACE2 in testicular tissue, leading to alterations in
testicular tissue and providing a site for viral infection (Cardona Maya et al., 2020) Following membrane
fusion, viral RNA is released into the cytoplasm, and viral replication begins
(Monteleone et al., 2020).
It has been considered that the main path for SARS-Cov-2 transmission is from person
to person through droplets and close contact (Chan et al., 2020). However, it has also been
hypothesized that other transmission routes may be available, although they require
further verification (Uddin et al.,
2020; Halfmann et al.,
2020). In reproductive medicine, special consideration has been paid as
to whether vertical transmission (mother-to-fetus)(Simões e Silva et al., 2020) and sexual transmission
may occur (Li et al.,
2020).
COVID-19 diagnosis and symptoms
The most frequently occurring symptoms of COVID-19 include fever, cough, fatigue,
shortness of breath, sputum production, headache, and myalgias. Patients may also
complain of vomiting, diarrhea, anosmia, and also ophthalmologic and cutaneous
manifestations (Segars et al.,
2020). Interestingly, in a recently published study evaluating the
presence of the coronavirus in the semen of infected patients, it was noted that
although no SARS-CoV-2 was identified in semen samples, ≈18% of infected men
reported scrotal discomfort at the time of COVID-19 infection (Pan et al., 2020).
COVID-19 patients have been classified as asymptomatic, mild, severe, and critical
types. Mild patients tend to experience mild pneumonia, while severe patients
exhibit dyspnea and increased respiratory frequency within 24-48 hours. Critical
patients suffer from respiratory failure, acute heart injury, septic shock, and
multiple organ failure (Mungroo et
al., 2020).
SARS-CoV-2 is a highly pathogenic virus that may be associated with uncontrolled
cytokine release, known as a cytokine storm, that may lead to capillary leakage,
tissue toxicity, edema, organ failure, and shock (Zhou et al. 2020). In COVID-19, a significant elevation
of cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α,
interleukin [IL]-6, IL-10, IL-2, IL-1, and others) and lymphocytopenia are found.
The clinical manifestation of the severe type in patients is significantly related
to elevated IL-6 (Zhou et al., 2020).
Although the presenting symptoms and radiographic analysis of computed tomography
(CT) scans may suggest the presence of COVID-19, a definitive diagnosis is achieved
through virus detection via polymerase chain reaction (PCR). It is recommended by
the U.S. Centers for Disease Prevention and Control (CDC) that a PCR is performed to
diagnose acute infection. False-positive SARS-CoV-2 testing is rare, although
false-negative results can occur due to inadequate sample collection or if it is
performed early in the disease course. PCR may be performed with samples obtained
from nasal swabs, trachea and nasopharynx extracts, and several primers used to
detect SARS-CoV-2, which were established through real-time reverse-transcription
(RT)-PCR. This enables fast and specific virus detection (Mungro et
al., 2020; ASRM COVID Task Force, 2020). Serologic tests, evaluating
the presence of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies are not
recommended for diagnosis of acute infection, although emerging evidence suggests
that they may confer immunity or reduced risk of reinfection. When performed by
ELISA, serologic tests present >95% specificity for disease diagnosis, but
sensitivity may range from 60%-98% (ASRM COVID Task Force, 2020).
SARS-CoV-2 and the male reproductive tract
• Does the virus affect the male reproductive tract?
Until now, it is unknown whether or to what extent SARS-CoV-2 can affect male
reproductive health (Wang & Xu, 2020; Esteves et al., 2020; Stanley et al., 2020).
COVID-19 is primarily contracted through droplets; however, the virus has already
been isolated in the urine (Guan et
al., 2020), feces (Guan et al., 202), and
conjunctiva (Xia et al. 2020) of infected patients. Due to its mechanism of action - i.e., ACE2
receptor binding - it may compromise other tissues with ACE2 receptors, such as
those of the reproductive system. Specifically, high ACE2 expression levels are
found in testicular cells, mainly in seminiferous duct cells, spermatogonia, and
Leydig and Sertoli cells (Esteves et al., 2020).
• Testicle
Studies of SARS-CoV reveal orchitis as a possible clinical presentation of this
virus, and there is evidence of deleterious effects on testicular tissues, including
the presence of the virus on autopsy (Xu et
al., 2006; Zhao et
al., 2003). As in SARS-CoV, the ACE2 receptor plays an
important role in the pathophysiology of SARS-CoV-2 infection, as it is used as the
primary form of cell binding, leading the virus to infect the cell and replicate.
Several studies have demonstrated a high concentration of ACE2 in testicular
tissues, either in germ cells or somatic cells (Fan et al., 2020; Wang & Xu, 2020; Shen et al., 2020; Zhang et al., 2020). Thus,
there is evidence that the testis is vulnerable to SARS-CoV-2 infection, so it is
important to assess and monitor the reproductive functions of these patients. In
addition, the presence of orchitis complaints was found in 19% of patients (Pan et al., 2020). However, a
recent study evaluated patients with COVID-19 and showed a complete absence of
SARS-COV-2 in the semen and testes of infected men (Song et al., 2020). Therefore, more studies examining
more patients are needed to confirm whether the virus is present in the testes.
• Prostate
Only one small retrospective study evaluated the presence of SARS-CoV-2 in prostatic
secretion (PS). A Chinese study evaluated the PS of 18 males diagnosed with COVID-19
and five suspected cases. The samples of all evaluated patients did not show
evidence of the RNA expression of SARS-CoV-2 (Quan et al., 2020).
• Seminal sample
Although there is a protective blood-testicular barrier, more than 27 viruses can be
found and transmitted through the semen, such as human immunodeficiency virus (HIV),
mumps, influenza, Zika virus, coxsackievirus infection, Ebola, and hepatitis B and
C. Two previous studies did not find SARS-CoV-2 in semen; however, these studies had
low numbers of patients who were at different stages of infection and recovery
(Pan et al., 2020; Song et al., 2020). The first
study to evaluate the semen of males diagnosed with COVID-19 evaluated 34 Chinese
males. Although six (19%) of these patients complained of scrotal discomfort due to
viral orchitis, SARS-CoV-2 was not detected in the semen of any of these patients
(Pan et al., 2020). The second study evaluated 12 patients in the
recovery phase of COVID-19, and the semen evaluation of all patients showed no
detectable SARS-CoV-2 RNA in the semen samples (Song et al.,
2020).
The third study published evaluating the semen samples of men with COVID-19 featured
38 patients. The study found that in six (15.8%) of these patients, SARS-CoV-2 was
detected in the semen samples, even among those who were recovering. However, the
study was not able to evaluate virus shedding, survival time, and viral
concentration in semen. This study raises question of whether SARS-CoV-2 can be
sexually transmitted, as this might represent a critical factor in transmission
prevention (Li et al.,
2020). Thus, as of May 15, 2020, data are available on the semen samples of
84 male patients with COVID-19, and it was found that SARS-CoV-2 was identified in
six (7.1%).
There are no data in the literature regarding changes in the fertile potential of
these men affected by SARS-CoV-2, although it is known that any feverish condition
is capable of altering seminal quality (Carlsen et al., 2003; Jung
& Schuppe, 2007). However, it is important to assess whether there
are any such direct effects associated with this virus, as occurs in cases of mumps
infection (Davis et al.,
2010).
• Hormonal dosages
There was an evaluation of gonadal function in some patients, which was achieved
through hormone profile measurement. When compared to healthy patients, those
infected showed a probable initial gonadotoxic effect (Zhang et al., 2020). However, more data are
necessary to confirm the gonadotoxic effects of the virus.
Conclusion
There is the theoretical possibility that testicular damage and subsequent
infertility may result following COVID-19 infection, and also the possibility of
sexual transmission, as SARS-CoV-2 has been identified in the semen of infected
patients. However, the available data and study findings are recent, based on small
sample sizes, and present conflicting information. Thus, until now, there is not
enough evidence to support the need for asymptomatic couples to avoid sexual
intercourse to protect against virus transmission. Further research is needed to
understand the long-term impacts of SARS-CoV-2 on male reproductive function,
including its potential effects on fertility and testicular endocrine function.
Before arriving at a definitive understanding of the impacts of potential viral
attacks on the testis, more detailed physiological and pathological examinations of
the male reproductive systems of COVID-19 patients after their recovery are needed.
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