Evaluating the impact of COVID-19 on male reproduction.

Invasion or damage of the male reproductive system is one of the reported outcomes of viral infection. Current studies have documented that SARS-CoV-2, which causes COVID-19, can damage the male reproductive system in large part by inflammatory damage caused by a cytokine storm. However, whether SARS-CoV-2 can infect the human testis directly and enter semen is controversial. Other adverse effects of SARS-CoV-2 on male reproduction are also of concern and require comprehensive evaluation. Here, we analyze the invasiveness of SARS-CoV-2 in the testis and examine reported mechanisms by which SARS-CoV-2 interferes with male reproduction. Long-term implications of SARS-CoV-2 infection on male reproduction are also discussed. It should be emphasized that although COVID-19 may induce testicular damage, a substantial decrease in male reproductive capacity awaits clinical evidence. We propose that there is an urgent need to track male COVID-19 patients during their recovery. The development of suitable experimental models, including human reproductive organoids, will be valuable to further investigate the viral impact on reproduction for current and future pandemics.

A coronavirus disease 2019 (COVID-19) patient with bilateral orchitis.

During the development of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), a myriad of complications has emerged and although rare, several genitourinary complications have been reported. The bulk of these complications have been secondary to hypercoagulable states, such as priapism. Previous SARS family infections have caused orchitis, though no adult cases of orchitis have been reported. We describe a novel case of SARS-CoV2 bilateral orchitis in a previously healthy 37-year-old male who presented for testicular pain with constitutional symptoms. Additionally, there was no epididymitis associated with the bilateral orchitis. Based on both data in SARS-CoV2 infected males and previous data from prior SARS infections, spermatocyte function may be compromised secondary to this infection. With the various symptoms associated with this virulent pathogen, we characterize the potential complications and importance of fertility follow up.

Review of COVID-19 and male genital tract.

COVID-19 pandemic leads to health challenges globally, and its diverse aspects need to be uncovered. Multi-organ injuries have been reported by describing potential SARS-CoV-2 entrance routes: ACE2 and TMPRSS2. Since these cell surface receptors' expression has been disclosed within the male reproductive system, its susceptibility to being infected by SARS-CoV-2 has been summarised through this literature review. Expression of ACE2 and TMPRSS2 at RNA or protein level has been reported across various investigations indicates that the male genitalia potentially is vulnerable to SARS-CoV-2 infection. Presence of SARS-CoV-2 within semen samples and following direct viral damage, secondary inflammatory response causing orchitis or testicular discomfort and finally the amount of viral load leading testicular damage and immune response activation are among probable underlying mechanisms. Therefore, genital examination and laboratory tests should be considered to address the male reproductive tract complications and fertility issues.

Potential mechanisms of SARS-CoV-2 action on male gonadal function and fertility: Current status and future prospects.

The novel coronavirus was recognised in December 2019 and caught humanity off guard. The virus employs the angiotensin-converting enzyme 2 (ACE2) receptor for entry into human cells. ACE2 is expressed on different organs, which is raising concern as to whether these organs can be infected by the virus or not. The testis appears to be an organ enriched with levels of ACE2, while the possible mechanisms of involvement of the male reproductive system by SARS-CoV-2 are not fully elucidated. The major focus of the present studies is on the short-term complications of the coronavirus and gains importance on studying the long-term effects, including the possible effects of the virus on the male reproductive system. The aim of this review was to provide new insights into different possible mechanisms of involvement of male gonads with SARS-CoV-2 including investigating the ACE2 axis in testis, hormonal alterations in patients with COVID-19, possible formation of anti-sperm antibodies (ASA) and subsequently immunological infertility as a complication of SARS-CoV-2 infection. Finally, we suggest measuring the sperm DNA fragmentation index (DFI) as a determiner of male fertility impairment in patients with COVID-19 along with other options such as sex-related hormones and semen analysis. Invasion of SARS-CoV-2 to the spermatogonia, Leydig cells and Sertoli cells can lead to sex hormonal alteration and impaired gonadal function. Once infected, changes in ACE2 signalling pathways followed by oxidative stress and inflammation could cause spermatogenesis failure, abnormal sperm motility, DNA fragmentation and male infertility.

SARS-CoV-2 and the testis: similarity with other viruses and routes of infection.

Since the start of the latest coronavirus (SARS-CoV-2) outbreak, the number of infected individuals and cases of coronavirus disease (COVID-19) has been increasing exponentially worldwide. Of interest is existing evidence that orchitis can develop due coronavirus infection. It is therefore not unreasonable to believe that SARS-CoV-2 could be transmitted by semen. Consequently, it is of paramount importance that individuals who could potentially be infected take all possible care to mitigate the likely risk of passing on the infection through sexual intercourse.

[Clinical characteristics of mumps infection in children and adult patients].

The aim of the article was to study clinical manifestations of mumps infection (infectious parotitis) - a viral illness that affects glands that produce saliva, pancreas, and nervous system in children and adult patients. 219 patients (42 children and 177 adults) with mumps infection were studied. The investigation showed that parotid salivary gland disorder was the most common in adults; sublinguitis - inflammation of the sublingual gland was the most common in children. Serous meningitis occurred exclusively in preschool and early school age. Pancreatitis was less common in children than in adults. Infectious parotitis involving the parotid salivary gland was taking its normal course with positive outcome. Pancreatitis and serous meningitis occurred at the 3-5 day of illness with infectious parotitis. Pancreatitis was with positive outcome, with the exceptions of adult patients with pain syndrome (repair process delayed to 1-1.5 months). Mean duration of hospitalization for children with infectious parotitis was 7 days, for adults - 10-14 days. Mean duration of hospitalization for patients with serous meningitis was 14 days. Study showed that in 20,1% of 16-27 years old males developed orchitis.

Whole Exome Sequencing Identifies a Rare Mutation in NACAD as a Possible Cause of COVID Orchitis in Brothers.

COVID orchitis (testicular pain) is reported in 10-15% of men with long COVID. We identified 2 siblings with COVID orchitis and hypothesized that genetic mutations are associated with susceptibility. Blood samples from 5 COVID-19 (+) men, three of whom had orchitis were evaluated by whole-exome-sequencing. A rare deletion on chromosome 7 was found in NACAD among the 3 men with orchitis. Interestingly, circulating ACE2 levels was decreased in men with COVID orchitis. This pilot study generated the hypothesis that men who develop COVID orchitis could have underlying genetic variants and altered levels in circulating ACE2 that may increase their risk.

Testicular pathology in fatal COVID-19: A descriptive autopsy study.

BACKGROUND: Multi-organ damage is a common feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, going beyond the initially observed severe pneumonia. Evidence that the testis is also compromised is growing. OBJECTIVE: To describe the pathological findings in testes from fatal cases of COVID-19, including the detection of viral particles and antigens, and inflammatory cell subsets. MATERIALS AND METHODS: Postmortem testicular samples were obtained by percutaneous puncture from 11 deceased men and examined by reverse-transcription polymerase chain reaction (RT-PCR) for RNA detection and by light and electron microscopy (EM) for SARS-CoV-2. Immunohistochemistry (IHC) for the SARS-CoV-2 N-protein and lymphocytic and histiocytic markers was also performed. RESULTS: Eight patients had mild interstitial orchitis, composed mainly of CD68+ and TCD8+ cells. Fibrin thrombi were detected in five cases. All cases presented congestion, interstitial edema, thickening of the tubular basal membrane, decreased Leydig and Sertoli cells with reduced spermatogenesis, and strong expression of vascular cell adhesion molecule (VCAM) in vessels. IHC detected SARS-Cov-2 antigen in Leydig cells, Sertoli cells, spermatogonia, and fibroblasts in all cases. EM detected viral particles in the cytoplasm of fibroblasts, endothelium, Sertoli and Leydig cells, spermatids, and epithelial cells of the rete testis in four cases, while RT-PCR detected SARS-CoV-2 RNA in three cases. DISCUSSION AND CONCLUSION: The COVID-19-associated testicular lesion revealed a combination of orchitis, vascular changes, basal membrane thickening, Leydig and Sertoli cell scarcity, and reduced spermatogenesis associated with SARS-CoV-2 local infection that may impair hormonal function and fertility in men.

Mumps Orchitis: Clinical Aspects and Mechanisms.

The causative agent of mumps is a single-stranded, non-segmented, negative sense RNA virus belonging to the Paramyxoviridae family. Besides the classic symptom of painfully swollen parotid salivary glands (parotitis) in mumps virus (MuV)-infected men, orchitis is the most common form of extra-salivary gland inflammation. Mumps orchitis frequently occurs in young adult men, and leads to pain and swelling of the testis. The administration of MuV vaccines in children has been proven highly effective in reducing the incidence of mumps. However, a recent global outbreak of mumps and the high rate of orchitis have recently been considered as threats to male fertility. The pathogenesis of mumps orchitis remains largely unclear due to lack of systematic clinical data analysis and animal models studies. The alarming increase in the incidence of mumps orchitis and the high risk of the male fertility have thus become a major health concern. Recent studies have revealed the mechanisms by which MuV-host cells interact and MuV infection induces inflammatory responses in testicular cells. In this mini-review, we highlight advances in our knowledge of the clinical aspects and possible mechanisms of mumps orchitis.

Case Report: A Rare Case of Crimean-Congo Hemorrhagic Fever Associated with Epididymo-Orchitis.

Crimean-Congo hemorrhagic fever (CCHF) is an acute infectious disease that affects multiple organ systems and is characterized by extensive ecchymosis, internal hemorrhage, and hepatic dysfunction. The reported case fatality rate varies between 8% and 80%. It is frequently transmitted by Hyalomma ticks, which are endemic in the Northeast Anatolia region of Turkey in spring and summer. Our patient presented from an endemic area with fever, malaise, joint pain, and scrotal pain following a tick bite, and real-time PCR analysis of venous blood was positive for CCHF. Based on Doppler ultrasound performed because of the patient's scrotal pain, he was diagnosed as having epididymo-orchitis, which was considered secondary to CCHF after ruling out other etiologies and resolved with scrotal elevation and anti-inflammatory treatment. Being a very rare complication, this report aimed to document this case of CCHF-associated epididymo-orchitis in the literature.

[SARS-CoV-2 infection: implications for sexual and reproductive health. A position statement of the Asociación Española de Andrología, Medicina Sexual y Reproductiva (ASESA)]. / Infección por SARS-CoV-2: implicaciones para la salud sexual y reproductiva. Una declaración de posición de la Asociación Española de Andrología, Medicina Sexual y Reproductiva (ASESA).

OBJECTIVE: The main objective of this revision is to summarize the current existing evidence of the potential adverse effects of SARS-CoV-2 on the male reproductive system and provide the recommendations of the Asociación Española de Andrología, Medicina Sexual y Reproductiva (ASESA) concerning the implications of COVID-19 infection in the management of male infertilty patients and testicular endocrine dysfunction. METHODS: A comprehensive systematic literature search of the databases of PubMed, Web of Science, Embase, Medline, Cochrane and MedRxiv, was carried out. RESULTS: The presence of orchitis as a potential complication of the infection by SARS-CoV-2 has not yet been confirmed. One study reported that 19% of males with COVID-19 infection had scrotal symptoms suggestive of viral orchitis which could not be confirmed. It is possible that the virus, rather than infecting the testes directly, may induce a secondary autoimmune response leading to autoimmune orchitis. COVID-19 has been associated with coagulation disorders and thus the orchitis could be the result of segmental vasculitis. Existing data concerning the presence of the virus in semen are contradictory. Only one study reported the presence of RNA in 15.8% of patients with COVID-19. However, the presence of nucleic acid or antigen in semen is not synonyms of viral replication capacity and infectivity. It has been reported an increase in serum levels of LH in males with COVID-19 and a significant reduction in the T/LH and FSH/LH ratios, consistent with subclinical hypogonadism. CONCLUSIONS: The findings of recent reports related to the potential effects of COVID-19 infection on the male reproductive system are based on poorly designed, small sample size studies that provide inconclusive, contradictory results. Since there still exists a theoretical possibility of testicular damage and male infertilty as a result of the infection by COVID-19, males of reproductive age should be evaluated for gonadal function and semen analysis. With regard to the sexual transmission of the virus, there is not sufficient evidence to recommend asymptomatic couples to abstein from having sex in order to protect themselves from being infected by the virus. Additional studies are needed to understand the long-term effects of SARS-CoV-2 on male reproductive function, including male fertility potential and endocrine testicular function.

Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known?

OBJECTIVE: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. DESIGN: Review of English publications in PubMed and Embase to April 6, 2020. METHOD(S): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. RESULT(S): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. CONCLUSION(S): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility.

Enzyme-Linked Immunosorbent Assay and Quantitative Reverse Transcription PCR as a Technique to Analyze Inflammation.

Inflammation is part of a defense reaction of live tissues that is triggered by pathogens, chemical reagents, trauma, and radiation. Understanding the inflammatory process triggered by Zika virus (ZIKV) is important to better understand the pathogen-host interaction. The evaluation of this process can be done using tools such as enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription PCR (RT-qPCR). Both techniques have been an indispensable tool not just for immunologists but for all interested in understanding the inflammatory process.

[Orchitis]. / Hodenentzündung.

Orchitis can be acutely symptomatic or chronically asymptomatic. Among the acute forms is the rarer isolated orchitis, which is of viral origin in most cases as well as the more frequent secondary orchitis, which is usually the result of an ascending bacterial epididymitis. In addition, sterile forms of orchitis are also seen in patients with systemic autoimmune comorbidities. Chronic asymptomatic orchitis is the term used to describe cellular immune infiltrates in the testes, which are observed in approximately 25% of cases of azoospermia during testicular biopsy. The etiopathogenesis of these infiltrates is largely unknown with postinfection and primary pathogen-independent autoimmune reactions being discussed. Animal experimental models of orchitis may be helpful to investigate the immunological mechanisms involved as well as the therapeutic possibilities.

Are we missing mumps epididymo-orchitis?

Mumps epididymo-orchitis has not been recorded as a cause of testicular symptoms without systemic features (including parotitis). The aim of the present study was to assess if we were missing cases in the genitourinary clinic during a previous outbreak of mumps in the community. During a prospective pilot study from November 2005 to February 2006, all patients presenting with symptoms or signs of epididymo-orchitis were studied. These patients were assessed for previous exposure to mumps virus or vaccine, and any current evidence of systemic illness. All patients included had a full sexual health screen (loop test, chlamydia polymerase chain reaction [PCR], gonorrhoea culture, HIV and Venereal Disease Research Laboratory [test]/Treponema pallidum particle agglutination assay), urinary tract infection excluded by urinalysis and mid-stream specimen of urine (MSSU) and mumps serology (Immunoglobulin M [IgM] and Immunoglobulin G [IgG]) performed. Twenty-three patients met inclusion criteria. Their ages ranged from 16 to 50 years, average 30.8 years. All had symptoms of these, 18 had testicular pain, eight swelling, (four had both pain and swelling) and three also had dysuria. On examination, 12 had tenderness, seven swelling, (two both tenderness and swelling) and six had no signs. Seventeen denied history of mumps, one patient had a record of vaccination and five described fever. None had parotid swelling. Three patients were chlamydia PCR positive, two had candida cultured, three had non-specific urethritis (>10 polymorphonuclear leucocyte/high powered field) and 13 had negative sexually transmitted infection screen (one known HIV-positive). Three had positive IgM mumps serology and two were IgG-positive. It is important to include mumps in the differential of epididymo-orchitis and to be aware of outbreaks in the community that may present with genital symptoms, as the management and partner notification will be different.

Orchitis in roosters with reduced fertility associated with avian infectious bronchitis virus and avian metapneumovirus infections.

The pathogenesis of infection involving both infectious bronchitis virus (IBV) and avian metapneumovirus (aMPV) causes reproductive damage in hens after viral replication in the epithelium of the oviduct, resulting in loss of cilia and degeneration and necrosis of the epithelial and glandular cells. Although IBV has been indicated as a possible cause of the formation of calcium stones in the epididymus of roosters, a definitive association has not been confirmed. This report describes the detection of IBV and aMPV in the testes of roosters from a Brazilian poultry broiler breeder's flock with epididymal stones and low fertility. Samples of testis, trachea, and lungs from breeder males aged 57 wk were positive for IBV by reverse transcriptase-polymerase chain reaction (RT-PCR), and virus isolation and testis samples were also positive for aMPV by RT-PCR. The inoculation of testis samples into embryonated chicken eggs via the allantoic cavity resulted in curled, hemorrhagic, and stunted embryos typical of IBV infection. The allantoic fluid was positive by RT-PCR aimed to amplify the region coding for the S1 subunit of the IBV S gene, but it was not positive for aMPV. Sequence analysis of the amplified fragment revealed a close relationship with European IBV genotype D274, previously unreported in Brazil. These results indicate that IBV and perhaps aMPV are likely to have played a role in the pathogenesis of the testicular disease described and should be regarded as factors that can influence male fertility disease in chickens.

[Mumps in patients hospitalized in Bydgoszcz in the years 1991-2003]. / Nagminne zapalenie przyusznic u chorych hospitalizowanych w Bydgoszczy w latach 1991-2003.

The case records of 1185 people, who were hospitalized because of epidemic parotitis at Department of Infectious Diseases in Bydgoszcz in the years 1991-2003 has been analyzed. An increase of the number of cases in the years: 1994, 1997/1998, 2003 has been indicated, especially in boys in the pre-school and school age. The most frequent complication in the course of mumps was meningitis, pancreatitis et orchitis. The only permament complication of the mumps was unilateral hypoacusis present in 5 patients. We observed that lumbar puncture is less frequently performed in cases of clinical mild neuroinfections in the course of mumps at the same we observed a tendency to shorten the time of hospitaliz ation to one week. In the light of conducted researches, the introduction of suggested vaccines against mumps does not seem to have had significant influence on the epidemiology of this disease.

Zika virus and reproduction: facts, questions and current management.

BACKGROUND: Zika virus (ZIKV) is an arthropod-borne virus of the family Flaviviridae, genus Flavivirus. ZIKV is currently the focus of an ongoing pandemic and worldwide public health emergency. Although originally isolated in 1947, its pathogenesis was poorly known and very few documented infections were published until recently. Its route of transmission and its impact on reproduction and pregnancy have only recently begun to be disclosed. OBJECTIVE AND RATIONALE: This review summarizes the most recent knowledge about ZIKV infection and pathogenesis and focuses on its impacts on male and female genital tracts, including the risks of sexual transmission and to pregnancy. The consequences of ZIKV infection for pregnancy planning and ART are also discussed. SEARCH METHODS: The PubMed and EMBASE databases were inter-rogated using specific terms, such as 'ZIKV', 'transmission', 'male', 'female', fertility', 'pregnancy, 'semen', 'testis', 'ovary' and 'genital tract', up to 17 March 2017. OUTCOMES: ZIKV has long been considered a harmless virus, but increasing evidence suggests that it has adverse effects on the neurological system and on pregnancy outcomes. In mice, ZIKV slows foetal growth and damages the foetal brain. In humans, the virus is able to cross the placental barrier and to induce foetal death and major anomalies, such as microcephaly, brain defects and long-term neurologic sequelae, i.e. the 'congenital Zika syndrome'. In addition to its transmission by mosquitoes, ZIKV may be transmitted sexually. Currently available data indicate that ZIKV RNA can remain detectable in semen for several months, whereas shedding in the female genital tract appears to be rare and of short duration. Current guidance on preventing the sexual transmission of ZIKV is based on the assumption that transmission occurs from a male partner to a receptive partner. Furthermore, in mouse models, the virus can actively replicate in male genital organs and induce severe orchitis, which raises concerns about its possible impact on human male fertility. WIDER IMPLICATIONS: These new and relevant findings have led many countries and institutions to release updated and regular guidance for preconception counselling and ART to prevent the sexual transmission of ZIKV. Progress in understanding the sexual transmission of ZIKV and its dissemination to genital systems would also help to better anticipate and control outbreaks of potentially sexually transmissible infectious agents.

Mumps orchitis.

Although the incidence of mumps orchitis has dramatically declined since the introduction of the childhood vaccination programme, a sharp increase in reported cases of both mumps and mumps orchitis has been seen recently in the UK. There are great concerns about mumps outbreaks and the associated risk of infertility; it remains an important clinical condition. Immunization is the best policy to avoid this viral disease.