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1.
PLoS Pathog ; 19(5): e1011409, 2023 05.
Article in English | MEDLINE | ID: covidwho-2323254

ABSTRACT

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.


Subject(s)
COVID-19 , Male , Mice , Animals , Humans , COVID-19/metabolism , Testis , SARS-CoV-2 , Bystander Effect , Inflammation/metabolism , Mice, Transgenic
2.
Int J Biol Sci ; 19(7): 2167-2197, 2023.
Article in English | MEDLINE | ID: covidwho-2314174

ABSTRACT

So far there has been no comprehensive review using systematic literature search strategies to show the application of single-cell RNA sequencing (scRNA-seq) in the human testis of the whole life cycle (from embryos to aging males). Here, we summarized the application of scRNA-seq analyses on various human testicular biological samples. A systematic search was conducted in PubMed and Gene Expression Omnibus (GEO), focusing on English researches published after 2009. Articles related to GEO data-series were also retrieved in PubMed or BioRxiv. 81 full-length studies were finally included in the review. ScRNA-seq has been widely used on different human testicular samples with various library strategies, and new cell subtypes such as State 0 spermatogonial stem cells (SSC) and stage_a/b/c Sertoli cells (SC) were identified. For the development of normal testes, scRNA-seq-based evidence showed dynamic transcriptional changes of both germ cells and somatic cells from embryos to adults. And dysregulated metabolic signaling or hedgehog signaling were revealed by scRNA-seq in aged SC or Leydig cells (LC), respectively. For infertile males, scRNA-seq studies revealed profound changes of testes, such as the increased proportion of immature SC/LC of Klinefelter syndrome, the somatic immaturity and altered germline autophagy of patients with non-obstructive azoospermia, and the repressed differentiation of SSC in trans-females receiving testosterone inhibition therapy. Besides, the re-analyzing of public scRNA-seq data made further discoveries such as the potential vulnerability of testicular SARS-CoV-2 infection, and both evolutionary conservatism and divergence among species. ScRNA-seq analyses would unveil mechanisms of testes' development and changes so as to help developing novel treatments for male infertility.


Subject(s)
COVID-19 , Infertility, Male , Adult , Humans , Male , Aged , Testis/metabolism , Spermatogenesis/genetics , COVID-19/metabolism , Hedgehog Proteins/metabolism , SARS-CoV-2/genetics , Infertility, Male/metabolism , Sequence Analysis, RNA
3.
Radiography (Lond) ; 29(4): 675-679, 2023 07.
Article in English | MEDLINE | ID: covidwho-2308241

ABSTRACT

INTRODUCTION: Testicular cells, seminiferous tubule cells, spermatogonia, Leydig and Sertoli cells showing angiotensin-converting enzyme 2 expression have the potential to be targets and to be damaged by the coronavirus. We aimed to use Two-Dimensional Shear Wave Elastography (2D-SWE) as an effective technique to identify parenchymal damage in the testicles of patients recovering from COVID-19 infection. METHODS: 35 Male patients (group 1) who recovered after COVID-19 infection between 4 and 12 weeks were included in this prospective study. Before 2D-SWE, these male patients were confirmed with control Rt-PCR test negativity. In addition, the first Rt-PCR test positivity of these patients was confirmed. A control group was formed of 31 healthy subjects (group 2). These two groups were compared in terms of age, volume of each testis, and SWE values. Ultrasound including SWE was applied to all the testes. A total of 9 measurements were taken as 3 SWE measurements from each third of the testis (superior, mid, inferior) and the average of these was calculated. Data obtained in the study were analyzed statistically. A value of p < 0.05 was accepted as statistically significant. RESULTS: The mean SWE values for the right testis and the left testis were determined to be statistically significantly higher in Group 1 than in Group 2, respectively (p < 0.001, p < 0.001). CONCLUSION: There is an increase in testicular stiffness in males who have recovered from COVID-19 infection. The underlying cause of testicular damage is changes at the cellular level. The 2D-SWE technique can predict potential testicular parenchymal damage in male patients recovering from COVID-19 infection. IMPLICATIONS FOR PRACTICE: Two-Dimensional Shear Wave Elastography (2D-SWE) seems to be a promising imaging technique in the evaluation of testis parenchyma.


Subject(s)
COVID-19 , Elasticity Imaging Techniques , Humans , Male , Testis/diagnostic imaging , Elasticity Imaging Techniques/methods , Prospective Studies , COVID-19/diagnostic imaging , Ultrasonography/methods
4.
Cells ; 12(8)2023 04 20.
Article in English | MEDLINE | ID: covidwho-2299159

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a SARS-like coronavirus, continues to produce mounting infections and fatalities all over the world. Recent data point to SARS-CoV-2 viral infections in the human testis. As low testosterone levels are associated with SARS-CoV-2 viral infections in males and human Leydig cells are the main source of testosterone, we hypothesized that SARS-CoV-2 could infect human Leydig cells and impair their function. We successfully detected SARS-CoV-2 nucleocapsid in testicular Leydig cells of SARS-CoV-2-infected hamsters, providing evidence that Leydig cells can be infected with SARS-CoV-2. We then employed human Leydig-like cells (hLLCs) to show that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 is highly expressed in hLLCs. Using a cell binding assay and a SARS-CoV-2 spike-pseudotyped viral vector (SARS-CoV-2 spike pseudovector), we showed that SARS-CoV-2 could enter hLLCs and increase testosterone production by hLLCs. We further combined the SARS-CoV-2 spike pseudovector system with pseudovector-based inhibition assays to show that SARS-CoV-2 enters hLLCs through pathways distinct from those of monkey kidney Vero E6 cells, a typical model used to study SARS-CoV-2 entry mechanisms. We finally revealed that neuropilin-1 and cathepsin B/L are expressed in hLLCs and human testes, raising the possibility that SARS-CoV-2 may enter hLLCs through these receptors or proteases. In conclusion, our study shows that SARS-CoV-2 can enter hLLCs through a distinct pathway and alter testosterone production.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Male , SARS-CoV-2/metabolism , COVID-19/metabolism , Testosterone/metabolism , Leydig Cells/metabolism , Testis/metabolism , Peptidyl-Dipeptidase A/metabolism
5.
Zool Res ; 44(3): 505-521, 2023 May 18.
Article in English | MEDLINE | ID: covidwho-2306427

ABSTRACT

Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.


Subject(s)
COVID-19 , Rodent Diseases , Zika Virus Infection , Zika Virus , Humans , Male , Mice , Animals , Testis , NF-kappa B/metabolism , COVID-19/veterinary , SARS-CoV-2/metabolism , Homeostasis , Fertility , Zika Virus/metabolism , Zika Virus Infection/metabolism , Zika Virus Infection/veterinary , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Phosphoproteins/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/pharmacology , Rodent Diseases/metabolism
6.
J Histochem Cytochem ; 71(4): 169-197, 2023 04.
Article in English | MEDLINE | ID: covidwho-2302515

ABSTRACT

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 RNA has been found in the human testis on occasion, but subgenomic SARS-CoV-2 and infectious SARS-CoV-2 virions have not been found. There is no direct evidence of SARS-CoV-2 infection of testicular cells. To better understand this, it is necessary to determine whether SARS-CoV-2 receptors and proteases are present in testicular cells. To overcome this limitation, we focused on elucidating with immunohistochemistry the spatial distribution of the SARS-CoV-2 receptors angiotensin-converting enzyme 2 (ACE2) and cluster of differentiation 147 (CD147), as well as their viral spike protein priming proteases, transmembrane protease serine 2 (TMPRSS2) and cathepsin L (CTSL), required for viral fusion with host cells. At the protein level, human testicular tissue expressed both receptors and proteases studied. Both ACE2 and TMPRSS2 were found in interstitial cells (endothelium, Leydig, and myoid peritubular cells) and in the seminiferous epithelium (Sertoli cells, spermatogonia, spermatocytes, and spermatids). The presence of CD147 was observed in all cell types except endothelium and peritubular cells, while CTSL was exclusively observed in Leydig, peritubular, and Sertoli cells. These findings show that the ACE2 receptor and its protease TMPRSS2 are coexpressed in all testicular cells, as well as the CD147 receptor and its protease CTSL in Leydig and Sertoli cells, indicating that testicular SARS-CoV-2 infection cannot be ruled out without further investigation.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Male , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , COVID-19/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Peptide Hydrolases/metabolism , Testis , RNA, Viral , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism
8.
Am J Mens Health ; 16(1): 15579883221074816, 2022.
Article in English | MEDLINE | ID: covidwho-2268849

ABSTRACT

With the global epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the increasing number of infections, little is known about how SARS-CoV-2 affects the male reproductive system during infection or after recovery. Based on the existing research data, we reviewed the effects of SARS-CoV-2 on the male reproductive system and discussed its possible mechanism of action. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme 2 (ACE2)/transmembrane serine protease 2 (TMPRSS2) pathway, and males are more susceptible than females. After infection, immunopathological damage is noticed in the testicles, and the semen index is significantly reduced. Second, abnormalities of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were also observed, suggesting that there may be dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. Even after recovery, the effect of SARS-CoV-2 on the male reproductive system can last for at least a period. There are still many unresolved questions about the effect of SARS-CoV-2 infection on the male reproductive tract. Other receptors involved during the invasion of human cells by SARS-CoV-2 remain to be identified. Will the mutation of SARS-CoV-2 increase the diversity of receptors? How does SARS-CoV-2 affect the HPG axis? The long-term effects of SARS-CoV-2 on the male reproductive system remain to be evaluated. SARS-CoV-2 infection can affect male reproductive function. Standard treatment strategies should be developed in time to protect the fertility of infected patients. For recovered patients with fertility requirements, fertility assessments should be performed and professional fertility guidance should be provided at the same time.


Subject(s)
COVID-19 , Female , Genitalia, Male , Humans , Male , Reproduction , SARS-CoV-2 , Testis
9.
BMC Biol ; 21(1): 36, 2023 02 16.
Article in English | MEDLINE | ID: covidwho-2255691

ABSTRACT

BACKGROUND: Cellular entry of SARS-CoV-2 has been shown to rely on angiotensin-converting enzyme 2 (ACE2) receptors, whose expression in the testis is among the highest in the body. Additionally, the risk of mortality seems higher among male COVID-19 patients, and though much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and potential consequences for reproductive health. We investigated testicular alterations in non-vaccinated deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the immune, vascular, and molecular fluctuations involved in the pathogenesis. RESULTS: We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensors or RT-qPCR using a specific methodology. Through an in vitro experiment exposing VERO cells to testicular macerates, we observed viral content in all samples, and the subgenomic RNA's presence reinforced the replicative activity of SARS-CoV-2 in testes of the severe COVID-19 patients. The cellular structures and viral particles, observed by transmission electron microscopy, indicated that macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites, where new virions form inside the endoplasmic reticulum Golgi intermediate complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient's infection. Further, we demonstrated high levels of angiotensin II and activated immune cells in the testes of deceased patients. The infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. CONCLUSIONS: Our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our findings suggest that patients who become critically ill may exhibit severe alterations and harbor the active virus in the testes.


Subject(s)
COVID-19 , Testis , Viral Tropism , Animals , Humans , Male , Angiotensin II/metabolism , Chlorocebus aethiops , COVID-19/pathology , SARS-CoV-2 , Testis/immunology , Testis/virology , Vero Cells
10.
J Genet Genomics ; 50(2): 99-107, 2023 02.
Article in English | MEDLINE | ID: covidwho-2239718

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 600 million people worldwide. Several organs including lung, intestine, and brain are infected by SARS-CoV-2. It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE2) is expressed in human testis. However, whether testis is also affected by SARS-CoV-2 is still unclear. In this study, we generate a human ACE2 (hACE2) transgenic mouse model in which the expression of hACE2 gene is regulated by hACE2 promoter. Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro, and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules. Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro. After testis interstitium injection, authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells, and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules. Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus. Attention should be paid to the reproductive function in SARS-CoV-2 patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Male , Mice , Animals , Testis/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Mice, Transgenic , Disease Models, Animal
11.
Biochemistry (Mosc) ; 86(4): 389-396, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-2078751

ABSTRACT

The novel coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health emergency worldwide with over 118.27-million confirmed COVID-19 cases and 2.62-million deaths recorded, as of March 12, 2021. Although this disease primarily targets lungs, damages in other organs, such as heart, kidney, liver, and testis, may occur. Testis is the cornerstone of male reproduction, while reproductive health is the most valuable resource for continuity of the human race. Given the unique nature of SARS-CoV-2, the mechanisms of its impact on the testes have yet to be fully explored. Notably, coronaviruses have been found to invade target cells through the angiotensin-converting enzyme 2 receptor, which can be found in the respiratory, gastrointestinal, cardiovascular, urinary tract, and reproductive organs, such as testes. Coronavirus studies have suggested that testes might be a potential target for SARS-CoV-2 infection. The first etiopathogenic concept proposed by current hypotheses indicates that the virus can invade testes through the angiotensin-converting enzyme 2 receptor. Next, the activated inflammatory response in the testes, disease-associated fever, and COVID-19 medications might be implicated in testicular alterations. Although evidence regarding the presence of SARS-CoV-2 mRNA in semen remains controversial, this emphasizes the need for researchers to pay closer attention to sexually transmitted diseases and male fertility after recovering from COVID-19. In this review the latest updates regarding COVID-19-associated testicular dysfunction are summarized and possible pathogenic mechanisms are discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fertility , Pandemics , SARS-CoV-2/metabolism , Testis/metabolism , COVID-19/mortality , COVID-19/pathology , Humans , Male , Testis/pathology , Testis/virology
12.
Andrologia ; 54(10): e14609, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2052227

ABSTRACT

This study aimed to examine the testicular functions with sperm analysis of patients with COVID-19. The study was carried out with male patients aged between 18 and 50 years with positive RT-PCR test and SARS-CoV-2 virus between December 2020 and April 2021. A total of 103 participants were included in the study. The mean age was 31.24 ± 5.67 (19-45) years and the mean body mass index of the participants was 28.41 ± 4.68 kg/m2 . The patients were divided into two groups, group-1 was patients who had COVID-19, group-2 was healthy men. A semen analysis of both groups was performed, and the serum total testosterone, FSH, LH, anti-mullerian hormone and Inhibin-B tests were analysed and recorded. The testicular dimensions and testicular densities were examined by ultrasound and elastography for both groups. Comparing the patient and control groups results, this study found that the sperm count per 1 cc (p = 0.01) and total motility (p = 0.01) in group-1 was lower than in the control group, the testicular dimensions decreased (for right testis group-2 was 15.39 ± 4.78 ml versus group-1 was 12.11 ± 4.62 cm3 p < 0.01, for left testis group-2 was 16.01 ± 5.12 versus group-1 was 11.92 ± 4.78 cm3 ; p < 0.01), and the shear wave velocities were significantly higher in group-1 patients. In conclusion, sperm parameters deteriorate in men who have symptomatic disease with SARS-CoV-2 infection. The fact that the cause of this deterioration is characterized by changes at the cellular level in the testis raises doubts about the persistence of this condition.


Subject(s)
COVID-19 , Testis , Adolescent , Adult , Anti-Mullerian Hormone , Follicle Stimulating Hormone , Humans , Inhibins , Luteinizing Hormone , Male , Middle Aged , SARS-CoV-2 , Semen , Semen Analysis , Sperm Count , Sperm Motility , Spermatozoa , Testis/diagnostic imaging , Testosterone , Young Adult
13.
Cells ; 11(17)2022 08 24.
Article in English | MEDLINE | ID: covidwho-1997528

ABSTRACT

Despite the major target of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, being the respiratory system, clinical evidence suggests that the male reproductive system may represent another viral target organ. Revealing the effect of SARS-CoV-2 infection on testis and sperm is a priority for reproductive biology, as well as for reproductive medicine. Here, we confirmed that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on human testis and ejaculated sperm; moreover, we provide evidence for the expression of the co-receptors transmembrane protease/serine (TMPRSS2), Basigin (BSG), and Catepsin L (CTSL). Human sperm were readily infected, both in vivo and in vitro, by SARS-CoV-2, as demonstrated by confocal and electron microscopy. The demonstration that the seminiferous epithelium and sperm support SARS-CoV-2 viral replication suggests the possibility that the spermatogenetic process may be detrimentally affected by the virus, and at the same time, supports the need to implement safety measures and guidelines to ensure specific care in reproductive medicine.


Subject(s)
COVID-19 , Humans , Male , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Semen/metabolism , Spermatozoa/metabolism , Testis/metabolism
14.
Int J Mol Sci ; 23(13)2022 Jun 28.
Article in English | MEDLINE | ID: covidwho-1934125

ABSTRACT

This Special Issue is intended to provide up-to-date information on reproduction, including the reproduction of germ cells and reproductive organs (ovary, testis, and uterus) [...].


Subject(s)
Reproduction , Testis , Female , Germ Cells , Humans , Male , Ovary , Uterus
15.
Medicine (Baltimore) ; 101(27): e29401, 2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1927459

ABSTRACT

Since SARS-CoV-2 infection was first discovered in December 2019 in Wuhan City in China, it spread rapidly and a global pandemic of COVID-19 has occurred. According to several recent studies on SARS-CoV-2, the virus primarily infects the respiratory system but may cause damage to other systems. ACE-2, the main receptor for entry into the target cells by SARS-CoV-2, was reported to abundantly express in testes, including spermatogonia, Leydig and Sertoli cells. Nevertheless, there is no clinical evidence in the literature about whether SARS-CoV-2 infection has an impact on male reproductive health. Therefore, this review highlights the effect of SARA-CoV-2 infection on male reproductive health, including the reproductive system and its functioning, as well as gamete and male gonadal function that might be affected by the virus itself or secondary to immunological and inflammatory response, as well as drug treatments and the psychological stress related to panic during the COVID-19 outbreak.


Subject(s)
COVID-19 , Infertility, Male , Humans , Infertility, Male/etiology , Male , Pandemics , SARS-CoV-2 , Testis
16.
Nat Rev Urol ; 19(7): 387-388, 2022 07.
Article in English | MEDLINE | ID: covidwho-1921628
17.
Clin Infect Dis ; 75(1): e974-e990, 2022 Aug 24.
Article in English | MEDLINE | ID: covidwho-1886373

ABSTRACT

BACKGROUND: The role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pathogenesis of testicular damage is uncertain. METHODS: We investigated the virological, pathological, and immunological changes in testes of hamsters challenged by wild-type SARS-CoV-2 and its variants with intranasal or direct testicular inoculation using influenza virus A(H1N1)pdm09 as control. RESULTS: Besides self-limiting respiratory tract infection, intranasal SARS-CoV-2 challenge caused acute decrease in sperm count, serum testosterone and inhibin B at 4-7 days after infection; and chronic reduction in testicular size and weight, and serum sex hormone at 42-120 days after infection. Acute histopathological damage with worsening degree of testicular inflammation, hemorrhage, necrosis, degeneration of seminiferous tubules, and disruption of orderly spermatogenesis were seen with increasing virus inoculum. Degeneration and death of Sertoli and Leydig cells were found. Although viral loads and SARS-CoV-2 nucleocapsid protein expression were markedly lower in testicular than in lung tissues, direct intratesticular injection of SARS-CoV-2 demonstrated nucleocapsid expressing interstitial cells and epididymal epithelial cells, While intranasal or intratesticular challenge by A(H1N1)pdm09 control showed no testicular infection or damage. From 7 to 120 days after infection, degeneration and apoptosis of seminiferous tubules, immune complex deposition, and depletion of spermatogenic cell and spermatozoa persisted. Intranasal challenge with Omicron and Delta variants could also induce similar testicular changes. This testicular damage can be prevented by vaccination. CONCLUSIONS: SARS-CoV-2 can cause acute testicular damage with subsequent chronic asymmetric testicular atrophy and associated hormonal changes despite a self-limiting pneumonia in hamsters. Awareness of possible hypogonadism and subfertility is important in managing convalescent coronavirus disease 2019 in men.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Animals , Cricetinae , Humans , Male , SARS-CoV-2 , Semen , Testis
18.
Eur Rev Med Pharmacol Sci ; 26(10): 3745-3750, 2022 05.
Article in English | MEDLINE | ID: covidwho-1876423

ABSTRACT

OBJECTIVE: We aimed to predict the potential testicular damage of COVID-19 by comparing the hormones FSH, LH, and TT before COVID-19 with values measured after COVID-19. PATIENTS AND METHODS: A total of 348 patients - who were followed up in our urology clinic for varicocele, premature ejaculation, erectile dysfunction and infertility, had FSH, LH and TT levels measured one year before COVID-19 and were positive for COVID-19 after a Polymerase Chain Reaction (RT-PCR) tests - were included in the study. Presence of pneumonia compatible with COVID-19, hospitalization in the intensive care unit and FSH, LH and TT values before and after COVID-19 were recorded, along with lung computed tomography (CT). RESULTS: The post-COVID-19 LH value (9.72±3.27 mIU/mL) of the patients was significantly higher than the pre-COVID-19 LH value (5.72±2.50 mIU/mL) (p<0.001). The post-COVID-19 TT (253.85±88.03 ng/dl) value was significantly lower than the pre-COVID-19 TT value (351.08±106.19 ng/dl) (p<.001). In addition, while there was a mean decrease of 127.8 ng/dl in TT level in patients with pneumonia, a decrease of 39.03 ng/dl was observed in patients without pneumonia (p<.001). CONCLUSIONS: COVID-19 may cause an increase in serum LH levels while decreasing TT levels. Additionally, those with COVID-19 pneumonia may experience a greater decrease in serum TT levels than those with COVID-19 without pneumonia.


Subject(s)
COVID-19 , Follicle Stimulating Hormone , Luteinizing Hormone , Testis , Testosterone , COVID-19/complications , Cross-Sectional Studies , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/blood , Male , Testis/diagnostic imaging , Testosterone/blood
19.
Andrology ; 10(6): 1047-1056, 2022 09.
Article in English | MEDLINE | ID: covidwho-1672955

ABSTRACT

BACKGROUND: The COVID-19 pandemic has led the international community to conduct extensive research into potential negative effects of the disease on multiple organs and systems in the human body. One of the most discussed areas is potential of the virus to compromise the testicular function. However, the lack of prospective studies on this topic makes it impossible to draw reliable conclusions on whether the disease affects the male reproductive system and, if so, to what extent. OBJECTIVES: The current trial is aimed at investigating the effect of SARS-CoV-2 on the testicular function, hormone levels and determining the extent of impact on spermatogenesis and damage to testicular tissue. MATERIALS AND METHODS: This prospective study included healthy controls and cases of patients suffering from viral pneumonia based on chest computed tomography (CT) and a positive SARS-CoV-2 throat swab exhibited moderate symptoms (World Health Organization (WHO) classification). Epidemiological, clinical, laboratory and ultrasound data were collected. A semen analysis was performed in cases during their hospital stay and 3 months after the discharge home. We also assessed the testicles obtained during autopsies of patients who died of COVID-19 (n = 20). RESULTS: A total of 88 participants were included (44 controls and 44 cases). Blood testosterone levels were significantly decreased in 27.3% of the cases (12/44). The mean level (7.3±2.7 nmol/L) was lower than that in the healthy controls (13.5±5.2 nmol/L, p < 0.001). An increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was also detected compared to the healthy controls (p = 0.04 and p = 0.002). The semen analysis revealed decreased motility in COVID-19 patients (p = 0.001), and a higher number of immobile sperm (during COVID-19: 58.8% and at 3 months 47.4%, p = 0.005). All parameters returned to normal at 3 months after discharge. Direct mixed agglutination reaction (MAR) test at 3 months showed an increase of Ig A (p = 0.03). In the majority of autopsies (18/20), structural disorders of the testicular tissue, with signs of damage to germ cells were observed. DISCUSSION AND CONCLUSION: COVID-19 and its management strategies significantly affect male hormone levels and sperm quality at the onset of the disease. Postmortem examination of testicular tissue confirmed inflammation and viral infiltration of the testicles. However, in patients with moderate to severe disease, the studied parameters of the testicular function returned to normal values within 3 months.


Subject(s)
COVID-19 , Follicle Stimulating Hormone , Humans , Luteinizing Hormone , Male , Pandemics , Prospective Studies , SARS-CoV-2 , Semen , Testis , Testosterone
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