key: cord-0874076-kot7abp6
authors: Patel, Darshan P.; Punjani, Nahid; Guo, Jingtao; Alukal, Joseph P.; Li, Philip S.; Hotaling, James M.
title: The impact of SARS-CoV-2 and COVID-19 on Male Reproduction and Men’s Health
date: 2021-01-01
journal: Fertil Steril
DOI: 10.1016/j.fertnstert.2020.12.033
sha: 76d3edd03ebdfb81e9da7e0bd9ea7f11b86a9fa0
doc_id: 874076
cord_uid: kot7abp6

Many couples initially deferred attempts at pregnancy or delayed fertility care due to concerns about the coronavirus disease 2019 (COVID-19). One significant fear during the COVID-19 pandemic was the possibility of sexual transmission. Many couples have since resumed fertility care while accepting the various uncertainties associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the evolving knowledge related to male reproductive health. Significant research has been conducted exploring viral shedding, tropism, sexual transmission, the impact of male reproductive hormones and possible implications to semen quality. However, to date, limited definitive evidence exists regarding many of these aspects, creating a challenging landscape for both patients and physicians to obtain and provide the best clinical care. This review provides a comprehensive assessment of the evolving literature surrounding COVID-19 and male sexual and reproductive health, and guidance for patient counseling.

Capsule: SARS-CoV-2 is unlikely to be detected in human semen, however viral tropism for the male reproductive tract and the impact on both male hormones and semen parameters remains incompletely characterized.

Many couples initially deferred attempts at pregnancy or delayed fertility care due to concerns about the coronavirus disease 2019 . One significant fear during the COVID-19 pandemic was the possibility of sexual transmission. Many couples have since resumed fertility care while accepting the various uncertainties associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the evolving knowledge related to male reproductive health. Significant research has been conducted exploring viral shedding, tropism, sexual transmission, the impact of male reproductive hormones and possible implications to semen quality. However, to date, limited definitive evidence exists regarding many of these aspects, creating a challenging landscape for both patients and physicians to obtain and provide the best clinical care. This review provides a comprehensive assessment of the evolving literature surrounding COVID-19 and male sexual and reproductive health, and guidance for patient counseling. Various microorganisms, including certain bacteria and viruses, may impact male reproductive function. As a result of direct testicular infection, men may have diminished sperm viability, reduced sperm counts, and impaired sperm motility, primarily through effects exerted on the testicles (2) (3) (4) . Viruses typically reach the testicle through hematogenous spread. Under normal circumstances, testicular immune privilege protects the testicular germ cells from the host inflammatory response to a systemic infection. However, certain viruses may cross the bloodtestis barrier and even invade testicular cells, eliciting an immune response within the testis (5).

A basic understanding of viral infection physiology is essential to understanding both the short and long-term impact of SARS-CoV-2 on male reproductive function. Figure 1 provides a broader overview of previously reported viral infections of the male reproductive tract (2) (3) (4) 6) .

We specifically review the impact of Mumps, human immunodeficiency virus (HIV), and Zika virus (viruses for which we have a basic understanding and known impact on male reproductive health) to frame the discussion regarding the impact of SARS-CoV-2 on male reproduction.

The Mumps virus is part of the Paramyxoviridae family of single-stranded RNA viruses (4, 7) .

The hallmark of Mumps is painful swelling of the parotid glands. Nearly 20-30% of post-pubertal men with Mumps develop unilateral epididymo-orchitis (7) . Bilateral orchitis occurs in approximately 15% of cases and can lead to testicular atrophy, reduced sperm concentration and motility, and even azoospermia. Reproductive impairment due to Mumps orchitis is thought to occur secondary to the induced host inflammatory response and its subsequent impact on Leydig and Sertoli cells' function as shown in in vitro mouse models (8, 9) . Infection of Leydig and Sertoli cells by the Mumps virus activates the innate immune response with the release of pro-inflammatory cytokines such as IFN-alpha and TNF-alpha (10) . Under these inflammatory conditions, impaired testosterone production and germ cell death can occur, although this mechanism is incompletely characterized (10) . Although the Mumps virus is primarily J o u r n a l P r e -p r o o f F & S ___ style revision transmitted by direct contact or respiratory droplets, it has been isolated previously in both human urine and semen (4) .

HIV belongs to the Lentivirus family and includes enveloped single-stranded RNA viruses (11) .

Acute HIV infection can cause symptoms of mild systemic viral illness followed by a period of clinical latency (11) . HIV has been detected in the semen after infection, and sexual transmission is the primary mode of transmission (12) . Large randomized trials have suggested that circumcision may reduce HIV transmission among heterosexual couples (13) . Leukocytes are the main vectors of HIV in the semen (12) . Progression to Acquired Immunodeficiency Syndrome (AIDS) is characterized by opportunistic infections and increased cancer risk due to viral immunosuppression (11) . Male patients with AIDS can develop chronic orchitis and hypogonadism (12) . HIV has also been found in testicular germ cells, however, the mechanism of viral entry remains poorly understood as the primary HIV receptor, CD4, is not found on testicular germ cells (12, 14) . The inflammatory response, impaired testosterone production by Leydig cells, and HIV infection of testicular germ cells can impact male reproductive and endocrine function (12, 14) .

The Zika virus is a single-stranded RNA virus that is part of the Flaviviridae family. The most severe clinical manifestations include Guillain-Barre syndrome and congenital microcephaly (15) .

Zika has been isolated in the semen and can be sexually transmitted (15, 16) . Interestingly, in men infected with Zika, viral levels are usually much higher in the semen as compared to serum levels, and may persist for over 188 days in the semen even though it is cleared in the serum after initial viral symptoms subside (16) . Given the relatively recent emergence of the Zika virus, there is limited data on the long term impact of Zika on human male reproductive and endocrine J o u r n a l P r e -p r o o f F & S ___ style revision function. In mouse models, Zika infection has been shown to cause significant epididymoorchitis leading to decreased sperm counts and diminished sperm motility (17) . In vitro models suggest that Zika predominantly infects Sertoli cells but also germ cells (18) .

Mumps, HIV, and Zika virus can lead to orchitis and have been detected in the semen. This poses many questions about the impact of SARS-CoV-2, also a single-stranded RNA virus on male reproductive health and detection in the semen.

SARS-CoV-2 is a single-stranded RNA virus of the coronavirus family. There are seven different coronaviruses that can infect humans (19) . The first four, 229E, NL63, OC43, and HKU1, cause mild viral symptoms (19) . The other three, SARS-CoV-1, MERS-CoV, and SARS-CoV-2, can cause more severe respiratory symptoms (19) . The SARS-CoV-2 envelope has 20 nm spikes that resemble a crown under electron microscopy, which gives the name coronavirus (20) .

SARS-CoV-2 has the largest genome among known RNA viruses (19) . Similar to other viruses, a nucleoprotein (N) surrounds the RNA genome to form a helical structure, which is surrounded by the viral envelope(E). The matrix protein (M) is embedded in the viral envelope, and the spike (S) proteins are anchored to the viral envelope. The S proteins are important for receptor recognition, cell attachment, and fusion during viral infection (21) . The S proteins are a trimeric glycoprotein found in all human coronaviruses and other viruses including HIV, influenza, and Ebola (21) .

Viral entry into host cells is mediated by the viral S proteins and the host cell receptor angiotensin-converting enzyme 2 (ACE2) (21) (22) (23) (24) . When the S protein binds to the ACE2 receptor, transmembrane protease serine 2 (TMPRSS2) found on the host cell surface, primes the S protein as well as other cellular protease to cleave the S protein into S1 and S2 subunits (22) . This critical step promotes viral entry into the host, as both ACE2 and TMPRSS2 are needed for viral entry. Once viral entry occurs, the viral RNA is released, and the viral genome's replication and transcription begins.

SARS-CoV-2 is primarily transmitted through respiratory droplets from infected individuals (25, 26) . The incubation period for COVID-19 ranges between 1-14 days after initial exposure, although most infected patients demonstrating symptoms of COVID-19 will manifest by day five after initial exposure (27, 28) . Once the virus is transmitted to an individual, SARS-CoV-2 begins replication within the airway epithelial cells. This is mediated primarily by the interaction between host ACE2 and TMPRSS2 discussed previously (22) . Infection of the airway epithelium can typically cause fevers, myalgia, sore throat, and shortness of breath (29) . In more severe cases, COVID-19 is characterized by severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock, and death (29) . Interestingly, the down-regulation of ACE-2 expression is associated with acute lung injury based on our understanding of SARS, but this may contribute to a gender susceptibility to COVID-19 as discussed below (30) . Additionally, alternative host cells with higher ACE-2 expression include enterocytes, which can lead to the gastrointestinal symptoms of COVID-19 such as diarrhea (29) .

reproductive health is the variability in COVID-19 severity and the immune response to SARS-CoV-2. It has been hypothesized that higher viral loads in the blood lead to hematogenous spread to the male reproductive tract and severe viral illness causing heightening host immune response within the testicle(4). Based on our knowledge of other viral illnesses (i.e. mumps), SARS-CoV-2 may impact male reproduction. Older age (>65 years), male gender, African

American and Asian race, diabetes, and hypertension are among many well established risk J o u r n a l P r e -p r o o f F & S ___ style revision factors for more severe symptoms and death from COVID-19 (31) (32) (33) . However, younger, healthy adults compromise 5% of all cases of severe COVID-19 (32) . Irrespective of these known risk factors, men are more likely to have more severe disease and clinical courses (33) .

Some hypotheses which are discussed later relate to differential expression of ACE2/TMPRSS (which have higher expression levels in the male specific organs), an androgen dependent relationship with higher levels possibly conferring worse disease, and/or innate immune differences in females which portend less significant disease (34, 35) .

Our understanding of the viral dynamics and the immune response is evolving but is relatively limited. The innate immune response requires recognition of SARS-CoV-2 as a pathogen. Host macrophages identify the pathogen-associated molecular patterns and viral RNA that activates innate immune response through interferon-1 (IFN-1) (36) . SARS-CoV-2 may exhibit immune evasion through inhibition of IFN-signaling pathways, which may contribute to variability in incubation periods (37) . Subsequent activation of the Natural Killer (NK) cells contribute to the innate immune response through a major histocompatibility complex (MHC) independent mechanism. Adaptive immunity against SARS-CoV-2 is initially mediated by cellular immunity through Helper T cells, which release IFN-γ tumor necrosis factor-α (TNFα), and interleukin-2 in response to antigen presentation by antigen presentation cells (APCs) (36) . The cytokine release by helper T cells activates cytotoxic T cells that attack and destroy virus-infected host cells (36) . Humoral immunity is another component of adaptive immunity that is mediated by B cells (36) . B cell activation leads to the production of IgM and IgG SARS-CoV-2 S-protein antibodies. There is variability in the timing of serum antibody production after initial infection, but an increase in levels of IgM and IgG SARS-CoV-2 S-protein antibodies is usually noted after ten days (38) . An improved understanding of the immune response to SARS-CoV-2 will help elucidate the gender susceptibility to COVID-19 and identify novel therapeutics.

Early epidemiologic studies from China suggested a significant male gender susceptibility for the rate of severe COVID-19 symptoms and mortality (32) . Similar trends have been seen in other countries as well (39) . Initially, this susceptibility was thought to be confounded by worse overall health status, chronic disease, and other lifestyle factors such as smoking (26) . However, two other theories have been proposed to explain the observed sex differences in COVID-19

outcomes. First, ACE2 is located on the short arm of the X chromosome, and therefore females have two copies. In normal development, one of the two X chromosomes is silenced in the late blastocyst stage of development, causing condensation of the X chromosome into a Barr body (40) . However, some genes escape this inactivation, which is more likely to occur on the short arm of the X chromosome where the ACE2 gene is located (40) . This may explain differences in ACE2 expression between different genders, although this finding has not been consistent in the literature (41) . Furthermore, ACE2 is a regulatory component of the reninangiotensin system, protecting against vascular compromise and severe organ damage. It is hypothesized that increased ACE2 expression in females is protective against more severe COVID-19 symptoms, as rapid viral saturation of ACE2 is less likely to occur (41) . The second theory to explain the sex differences in COVID-19 symptoms and outcomes is the association between TMPRSS2 and androgen sensitivity. The androgen response element is a transcriptional promoter for TMPRSS2, which was initially described in the context of the TMPRSS2-ERG fusion gene and prostate oncogenesis (42) . It is believed that lower levels of circulating androgens in females lead to lower cellular expression levels of TMPRSS2 and downregulation of this host receptor. Although early epidemiologic studies have suggested that males are at higher risk of more severe COVID-19 and mortality, causal mechanisms remain unknown, and require further investigation.

Severe COVID-19 and mortality have also been documented in healthy young adults. This has led to investigations into genetic variants that may confer a more severe COVID-19 course due to a subclinical primary immunological defect. Van der Made et al. reported a study of four young, healthy males (pairs of brothers) with severe COVID-19 admitted to the intensive care unit in the Netherlands (43) . Whole-genome sequencing identified loss-of-function variants of the TLR7 gene on the X-chromosome. Functional testing in primary immune cells of these brothers suggested the downregulation of Type I and Type II IFN signaling. As discussed previously, the IFN pathway is important in the innate immune response and subsequent activation of NK cells.

These novel findings suggest that genetic variants may also impact the severity of COVID-19 and male gender susceptibility, although this warrants further investigation.

COVID-19 has also had impacts to sexual function and sexual activity. Early in the pandemic it was reported in a study from China that sexual frequency had decreased in 37% of those surveyed, and 44% reported a decrease in the number of sexual partners (44) . Interestingly a study from Bangladesh, India and Nepal suggested minimal change in sexual activity and perhaps even an increase in frequency in a small subset (45) . Sexual practices during COVID-19 may be impacted through social isolation leading to changes in mood as well as fear of transmission. It has also been suggested that cardiovascular disease from COVID-19 and subsequent treatment may lead to erectile dysfunction and neurological manifestations from cerebrovascular disease or hemorrhage may impact sexual desire as well as erectile and ejaculatory function (46) . Other sexual practice related issues also continue to be explored including self-stimulation practices and pornography usage during the pandemic (44) . (48) . They found that patients with COVID-19 had higher serum luteinizing hormone (LH) levels and decreased testosterone: LH ratio compared to controls but there was no statistical difference in serum testosterone levels in cases compared to controls (3.97ng/mL in cases versus 4.79ng/mL in controls). No differences were also seen for estradiol, but there were significant increases in prolactin levels. Additionally, on multivariable analyses, serum testosterone: LH ratio among cases was negatively associated with serum white blood cell count and C-reactive protein levels. Another study by Rastrelli et al. described the association between testosterone levels and clinical outcomes after severe COVID-19 (49) . They reported on 31 male patients with SARS-CoV-2 pneumonia in a respiratory care unit where men were categorized into different cohorts based on increased/decreased levels of care and/or mortality. Men who required a higher level of care or died had lower total serum testosterone levels than those who recovered clinically. Additionally, an increase in mortality and intensive care unit transfer was seen in men with total testosterone <5 nmol/L. These data have not been reproduced in large scale prospective trials.

Additional studies have explored this androgen hypothesis for COVID-19. In a report of 41 men from Spain they reported that 71% of those admitted to hospital with COVID-19 had androgenetic alopecia (male pattern hair loss), which is a known androgen mediated J o u r n a l P r e -p r o o f F & S ___ style revision phenomenon (50) . Since the androgen receptor is also composed of trinucleotide repeats (CAG) it has been hypothesized that this may be implicated in some of the variable disease courses for COVID-19 (51) . To further corroborate an androgen hypothesis, data from a large Italian series of 4532 men, demonstrated that men with prostate cancer who received androgen depravation therapy (ADT) had significantly lower risks of disease when compared to those without ADT, and this difference was more significant when compared with any other malignancies (52) . While this study was conducted in a specific subset of men, it has suggested a protective effect of ADT in COVID-19 outcomes and prompted some to consider clinical trials of ADT.

Host cell co-expression of ACE2 and TMPRSS2 for S protein priming is a critical component of viral entry. ACE converts angiotensin I to angiotensin II and is predominantly found in the lung, intestine, heart, and kidney (23, 24) . TMPRSS2 is found predominantly in the gastrointestinal tract, genitourinary tract, and the prostate (42) . It is still uncertain whether the male reproductive system is susceptible to SARS-CoV-2 infection, primarily since both ACE2 and TMPRSS2 coexpression are needed by an individual host cell to facilitate viral entry and it is unclear how frequently these are co-expressed (22, 53) .

To evaluate the immediate and long-term impact of COVID-19 on testis and male reproduction, pathological examination of the testes tissues from COVID-19 patients during and post recovery will be very useful. Traditional approaches utilizing histological examination can provide a general understanding of how SARS-CoV-19 infection impacts the testis physiology, and subsequent reproductive health. However, more systematic approaches are also needed to explore the impact of human testis in order to bring in molecular and mechanistic insights.

Single-cell RNA Sequencing (scRNA-seq) can serve as a very useful tool for such purposes. (60) . SARS-CoV-2 was found in all patients' respiratory tracts, postmortem; however, it was not found in the testis (60) . Microscopic findings from the testis showed sloughing of the spermatocytes, elongation of spermatids, and swelling and vacuolization of Sertoli cells suggestive of an acute testicular injury (Figure 3) . In two cases, they found multifocal micro thrombi in the testicular vasculature, which has also been shown in lung tissue after SARS-CoV- 

There is relatively limited evidence regarding SARS-CoV-2 tropism for the epididymis, seminal vesicles, and prostate. Bioinformatics analysis from The Human Protein Atlas database (68) . They found that 0.32% and 18.65% of prostate epithelial cells expressed ACE2 and TMPRSS2, respectively, however co-localization was identified in <1% of cells (68) . Pathologic evaluation of prostate tissue in men recovering from COVID-19 has not been explored.

Recently, there have been many reports regarding the detection of SARS-CoV-2 in the semen of patients previously diagnosed with COVID-19. Based on the current literature, the majority of the reports suggest that SARS-CoV-2 is not detected in the semen (48, 54, 66, (69) (70) (71) (72) (73) . These findings are summarized in Table 1 

At this time limited data exists on the implications for children born to men who were infected with COVID-19. Current evidence from the Society for Maternal Fetal Medicine suggests minimal risk of vertical transmission from mother to their newborn but there is concern for respiratory transmission to a new fetus (76) . In the few cases of vertical transmission discussion has occurred regarding whether the nature of transmission (i.e. transplacentally or transcervically) (77) . Longitudinal studies are needed to further assess the long-term impacts of children born to parents with history of COVID-19 infection.

Many reproductive care centers have resumed fertility care delivery after both risk assessment and mitigation, consideration for resource availability, and careful counseling. Beginning in (https://www.sart.org/globalassets/__sart/covid-19/labguidanceupdate1.pdf). We recommend referring to these guidelines and guidance from the Centers for Disease Control (CDC), about the delivery of fertility care during the COVID-19 pandemic. Furthermore, due to restrictions during the pandemic, many clinicians treating patients with infertility adopted telemedicine in order to continue to provide care to these patients. This has been supported by the Society of Male Reproductive Urologists (https://connect.asrm.org/smru/forprofessionals/new-item/newitem?ssopc=1). These guidelines however do reinforce the importance of physical examination for patient assessment and the use of adjunctive tests when required.

One of the most significant considerations regarding SARS-CoV-2 and male reproductive health is collection, handling, and preservation of semen samples. There is currently limited evidence suggesting that SARS-CoV-2 can be isolated from the semen of a recovered male or asymptomatic male with SARS-CoV-2 infection. Efforts should be made to screen patients for possible signs and symptoms of COVID-19 or recent exposures to someone diagnosed with COVID-19 before on-site semen sample collection. In previously symptomatic patients who recovered from COVID-19, the CDC recommends discontinuation of isolation once at least ten days have passed since symptom onset, at least 24 hours have passed since the resolution of fever, and other COVID-19 symptoms are improved (https://www.cdc.gov/coronavirus/2019ncov/hcp/duration-isolation.html). In patients infected with SARS-CoV-2 who did not demonstrate any COVID-19 symptoms, isolation may be discontinued ten days after their first positive RT-PCR test. Every effort should be made to protect the health of all patients, staff J o u r n a l P r e -p r o o f F & S ___ style revision members, and healthcare providers by strict adherence to infection prevention and control measures such as hand hygiene, social distancing, environmental infection control, and appropriate use of personal protective equipment. Semen collection labs may consider off-site semen collection if feasible, including at-home collection following standard protocols.

Furthermore, appropriate risk assessment and mitigation strategies should be employed by the reproductive care center to handle semen samples from patients. Currently, the CDC recommends using eye protection or face shield, medical-grade gloves, and medical-grade mask in the handling of all body fluids, including semen, by staff members (https://www.cdc.gov/hai/pdfs/ppe/ppeslides6-29-04.pdf). Although the primary potential risk to staff would be through semen samples' splashing, every effort should be made to prevent aerosol formation during the procedure, such as pipetting, centrifugation, and mixing. If possible, a physically separate space and dedicated instruments/equipment should be used for semen samples from patients recovered from COVID-19. Another consideration includes the cryopreservation of semen or testicular samples from recovered COVID-19 patients and use for ART. Currently, there is no indication for routine testing of semen samples for SARS-CoV-2 using RT-PCR before cryopreservation or ART. There is no evidence for any specific microbicide or processing protocol to protect against possible viral transmission from a recovered male. However, published protocols for handling semen samples and performing ART from individuals infected with HIV or the Hepatitis virus may be employed as an additional precaution but this practice may vary between laboratories(78). Although viral crosscontamination between different preserved samples has never been reported, use of highsecurity straws and segregated cryo-vessels should be considered if possible for semen samples or testicular tissue from recovered COVID-19 patients. 

Role of oxidative stress, infection and inflammation in male infertility

Bacterial infection of the male reproductive system causing infertility

Microbiological investigation in male infertility: a practical overview

Viruses in the mammalian male genital tract and their effects on the reproductive system

Testicular defense systems: immune privilege and innate immunity

The Breadth of Viruses in Human Semen

Mumps orchitis

Mumps virus-induced innate immune responses in mouse Sertoli and Leydig cells

Mouse Testicular Cell Type-Specific Antiviral Response against Mumps Virus Replication

Tumour necrosis factor-alpha released by testicular macrophages induces apoptosis of germ cells in autoimmune orchitis

Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

HIV-1 Populations in Semen Arise through Multiple Mechanisms

Circumcision and its effects in Africa

Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance

Zika Virus: An Emerging Global Health Threat

Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen?

Zika virus causes testicular atrophy

Sertoli Cells Are Susceptible to ZIKV Infection in Mouse Testis

Coronaviruses: an overview of their replication and pathogenesis

SARS: clinical virology and pathogenesis

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Detection of SARS-CoV-2 in Different Types of Clinical Specimens

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application

of Novel Coronavirus-Infected Pneumonia

A Novel Coronavirus from Patients with Pneumonia in China

Angiotensin-converting enzyme 2 in lung diseases

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Clinical Characteristics of Coronavirus Disease 2019 in China

Outcome Disparities Among Men and Women With COVID-19: An Analysis of the New York City Population Cohort

The immune system in menopause: pros and cons of hormone therapy

Sex Drives Dimorphic Immune Responses to Viral Infections

Molecular immune pathogenesis and diagnosis of COVID-19

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19

Are we equal in adversity? Does Covid-19 affect women and men differently?

Genes that escape from X inactivation

Correction: Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats

TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells

Presence of Genetic Variants Among Young Men With Severe COVID-19

How Is the COVID-19 Pandemic Affecting Our Sexualities? An Overview of the Current Media Narratives and Research Hypotheses

Does COVID-19 pandemic affect sexual behaviour? A cross-sectional, cross-national online survey

A focused review on the genital and sexual affection of COVID-19 patients

Androgens and energy allocation: quasi-experimental evidence for effects of influenza vaccination on men's testosterone

Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients

Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients

A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain -A potential clue to the role of androgens in COVID-19 severity

Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19

Androgendeprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a populationbased study (N = 4532)

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019

Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2

A Target for SARS-CoV-2 Infection in Spermatogonia

Single-cell transcriptome analysis of the novel coronavirus (SARS-CoV-2) associated gene ACE2 expression in normal and nonobstructive azoospermia (NOA) human male testes

Orchitis: a complication of severe acute respiratory syndrome (SARS)

COVID-19 Autopsies

Testicular Changes Associated with SARS-CoV-2. Archives of pathology & laboratory medicine

Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications

Abdominal and testicular pain: An atypical presentation of COVID-19

patient with bilateral orchitis: A case report. The American journal of emergency medicine

Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis

Assessment of SARS-CoV-2 in human semen-a cohort study

Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer

Expression of ACE2, the SARS-CoV

Receptor, and TMPRSS2 in Prostate Epithelial Cells

Absence of 2019 Novel Coronavirus in Semen and Testes of COVID-19 Patients

Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab

Absence of SARS-CoV-2 in semen of a COVID-19 patient cohort

Italian males recovering from mild COVID-19 show no evidence of SARS-CoV-2 in semen despite prolonged nasopharyngeal swab positivity

Investigation of SARS-CoV-2 in Semen of Patients in the Acute Stage of COVID-19 Infection

Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease

The absence of coronavirus in expressed prostatic secretion in COVID-19 patients in Wuhan city

Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis

Transplacental transmission of SARS-CoV-2 infection

Guidelines for risk reduction when handling gametes from infectious patients seeking assisted reproductive technologies

The authors would like to thank Brenna Kelly for graphic design assistance. NP is supported by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust.J o u r n a l P r e -p r o o f

Host TMPRSS2 primes the viral S protein as cellular proteases cleave the S protein in S1 and S2 subunits.