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Proceedings of the National Academy of... Nov 2021Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected...
Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration-approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and β-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in and mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.
Topics: Animals; Epididymitis; GTP-Binding Protein alpha Subunits, Gq-G11; Infertility, Male; Lipopolysaccharides; Male; Mice, Inbred C57BL; Mumps virus; Orchitis; Receptor, Parathyroid Hormone, Type 1; beta-Arrestin 1; Mice
PubMed: 34740971
DOI: 10.1073/pnas.2107363118 -
Reproductive Medicine and Biology Jan 2020The testis is specific in that it produces haploid germ cells of which autoantigens newly appear long after the neonatal immune tolerance. Under normal condition, these... (Review)
Review
BACKGROUND
The testis is specific in that it produces haploid germ cells of which autoantigens newly appear long after the neonatal immune tolerance. Under normal condition, these autoantigens are protected by the blood-testis barrier formed by Sertoli cells. Thus, the testis is an immunologically privileged site where haploid cells are protected from autoimmune attack.
METHODS
The immunological microenvironment in the testis was experimentally investigated using mice and rats.
MAIN FINDINGS
Not only the blood-testis barrier but also various immuno-suppressive factors are involved in the immune-privileged testis. Indeed, germ cells transplanted into the xenogeneic seminiferous tubules could proliferate and differentiate with no aid of artificial immunosuppression. On the other hand, autoimmune orchitis could be experimentally produced by various methods of immunization with syngeneic or xenogeneic germ cell antigens.
CONCLUSION
Our results indicate that the testis is immunologically privileged but also immunologically fragile organ. Therefore, the dual nature is critical for immunoregulation of testicular function.
PubMed: 31956282
DOI: 10.1002/rmb2.12293 -
Journal of Family Medicine and Primary... Sep 2022Blood-testis barrier is body's innate mechanism to defend germ cells by creating a physical and immunological barrier. But some viral infections are known to evade it.... (Review)
Review
Blood-testis barrier is body's innate mechanism to defend germ cells by creating a physical and immunological barrier. But some viral infections are known to evade it. As ACE2 and TMPRSS2 are present all over the body including male reproductive tract, it is worth exploring how coronavirus disease (COVID-19) could possibly affect male fertility. A review of literature was done using search engines like PubMed, Medline, Google Scholar, etc., and all the latest articles up to May 2021 were considered. Some studies have substantiated the presence of orchitis in COVID patients using semen and tissue samples. Though most studies report the absence of virus in testis, involvement of seminiferous tubules has been seen in pathological analysis suggesting defective spermatogenesis. This can be primarily attributed to inflammation and increased vascular permeability. Other factors that could affect male fertility are fever, autoimmune response, drugs, and erectile dysfunction. Male fertility is an important aspect of health care and must be looked into. Further studies can be done to understand host immunity towards SARS-CoV-2 in the testis. It will be worthwhile to know whether viral orchitis and its sequelae are acute or chronic in nature, and if they are reversible. Effect of the virus on female reproductive tract can also be assessed further. Counselling can be given to affected/recovering patients along with correct selection of drugs to prevent these long-term complications.
PubMed: 36505593
DOI: 10.4103/jfmpc.jfmpc_199_22 -
International Journal of Molecular... Dec 2020The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens,... (Review)
Review
The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility.
Topics: Animals; Autoimmunity; Biomarkers; Disease Management; Disease Susceptibility; Homeostasis; Humans; Immunity; Immunomodulation; Leydig Cells; Male; Sertoli Cells; Spermatogenesis; T-Lymphocyte Subsets; T-Lymphocytes; Testis
PubMed: 33374605
DOI: 10.3390/ijms22010057 -
Andrology Sep 2021Scrotal ultrasonography is an essential diagnostic tool in daily clinical practice. The availability of new-generation ultrasound machines characterized by clearly... (Review)
Review
BACKGROUND
Scrotal ultrasonography is an essential diagnostic tool in daily clinical practice. The availability of new-generation ultrasound machines characterized by clearly improved image quality, low health cost, and higher patient safety, represents only some characteristics of ultrasound investigation. The usefulness of scrotal ultrasonography is particularly evident in the period of life from infancy to puberty, during which males undergo important morphofunctional changes, and several pathological conditions may occur.
OBJECTIVES
This pictorial review primarily aimed to investigate the aspects of ultrasonography related to the normal physiological development of the gonads from mini-puberty to pubertal onset. This study also aimed to provide an update on the use of ultrasonography in main andrological pathologies that may occur during this period. The conditions that are discussed in depth are: cryptorchidism, inguinoscrotal hernias, and hydrocele in the neonatal phase; acute scrotum, epididymo-orchitis, and testicular cancers in childhood; and hypogonadism, varicoceles, testicular microlithiasis, and oncohematological pathology in puberty.
DISCUSSION
We provided an ultrasound slant for all the above-mentioned pathologies while purposely avoiding excessive deepening of the pathogenetic, clinical, and therapeutic aspects. Studying the ultrasound aspects of the gonads also facilitates differential diagnosis between various conditions and represents a good aid in evaluating therapeutic success (e.g., in hypogonadism or postsurgical evaluation of varicoceles and cryptorchidism).
CONCLUSION
Scrotal ultrasonography is now globally recognized as the necessary completion of clinical-laboratory overview in gonads evaluation. This diagnostic procedure is even more indispensable in the infancy-childhood-puberty period for the evaluation of normal gonadal development as well as diagnosis of other possible diseases.
Topics: Adolescent; Child; Child, Preschool; Genital Diseases, Male; Humans; Infant; Infant, Newborn; Male; Medical Illustration; Puberty; Scrotum; Ultrasonography
PubMed: 34048149
DOI: 10.1111/andr.13056 -
Cancers Aug 2022Testicular tumours are the most common tumours found in young males and germ cell tumours account for 95% of testicular tumours. Ultrasound is the first-line... (Review)
Review
Testicular tumours are the most common tumours found in young males and germ cell tumours account for 95% of testicular tumours. Ultrasound is the first-line radiological investigation for imaging of the testis. This article outlines how to undertake an ultrasound examination, including optimal patient position, scanning technique and imaging parameters. Classification of germ cell tumours is provided, and salient imaging features of different tumours are described. Difficulties and pitfalls of ultrasound are described, including tumours found after a trauma presentation, orchitis causing diagnostic difficulties and imaging of small testicular lesions. Other uses of ultrasound are outlined, including looking for a primary testicular tumour following the discovery of retroperitoneal lymph nodes, imaging when tumour-makers increase, local recurrence in the scrotum, and for solid organ biopsy in metastatic disease. Conclusion: Ultrasound remains the first-line of investigation for imaging of the testis, and conventional ultrasound still plays a large role in imaging. On ultrasound alone, accurate morphological characterisation of tumours remains a challenge, despite the imaging features that can be seen in different tumour types. Therefore, histology following orchidectomy of a germ cell tumour remains the gold standard for accurate tumour characterisation.
PubMed: 36010875
DOI: 10.3390/cancers14163882 -
EClinicalMedicine Nov 2020The current study aimed to determine the impact of SARS-CoV-2 infection on male fertility.
BACKGROUND
The current study aimed to determine the impact of SARS-CoV-2 infection on male fertility.
METHODS
This is a single-center, hospital-based observational study that included autopsied testicular and epididymal specimens of deceased COVID-19 male patients (=6) and recruited recovering COVID-19 inpatients (=23) with an equal number of age-matched controls, respectively. We performed histopathological examinations on testicular and epididymal specimens, and also performed TUNEL assay and immunohistochemistry. Whereas, we investigated the semen specimen for sperm parameters and immune factors.
FINDINGS
Autopsied testicular and epididymal specimens of COVID-19 showed the presence of interstitial edema, congestion, red blood cell exudation in testes, and epididymides. Thinning of seminiferous tubules was observed. The number of apoptotic cells within seminiferous tubules was significantly higher in COVID-19 compared to control cases. It also showed an increased concentration of CD3+ and CD68+ in the interstitial cells of testicular tissue and the presence of IgG within seminiferous tubules. Semen from COVID-19 inpatients showed that 39.1% (=9) of them have oligozoospermia, and 60.9% (=14) showed a significant increase in leucocytes in semen. Decreased sperm concentration, and increased seminal levels of IL-6, TNF-α, and MCP-1 compared to control males were observed.
INTERPRETATION
Impairment of spermatogenesis was observed in COVID-19 patients, which could be partially explained as a result of an elevated immune response in testis. Additionally, autoimmune orchitis occurred in some COVID-19 patients. Further research on the reversibility of impairment and developing treatment are warranted.
FUNDING
This study was supported by Ministry of Science and Technology of China Plan, Hubei Science and Technology Plan, National Key Research and Development Program of China, HUST COVID-19 Rapid Response Call, China and National Natural Science Foundation of China; these funding bodies are public institutions, and they had no role in study conception, design, interpretation of results, and manuscript preparation.
PubMed: 33134901
DOI: 10.1016/j.eclinm.2020.100604 -
Viruses Sep 2021Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is... (Review)
Review
Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its entry, interaction with host factors, and host-cell immune responses. Although the underlying mechanisms of MuV tropism remain to be fully understood, recent studies on virus-host interactions have provided insights into viral pathogenesis. This review was aimed at summarizing the entry process of MuV by focusing on the glycan receptors, particularly the recently identified receptors with a trisaccharide core motif, and their interactions with the viral attachment proteins. Here, we describe the receptor structures, their distribution in the human body, and the recently identified host factors for MuV and analyze their relationship with MuV tropism.
Topics: Host-Pathogen Interactions; Humans; Mumps; Mumps virus; Protein Binding; Receptors, Virus; Viral Proteins; Viral Tropism; Virus Attachment; Virus Internalization
PubMed: 34578327
DOI: 10.3390/v13091746 -
Andrology Jul 2021Coronavirus disease 2019 (COVID-19), which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid-December 2019 in China and... (Review)
Review
BACKGROUND
Coronavirus disease 2019 (COVID-19), which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid-December 2019 in China and has spread around the world. In addition to causing serious respiratory illnesses such as pneumonia and lung failure, there have been conflicting reports about the presence of SARS-CoV-2 in the semen of patients who were previously diagnosed with COVID-19 and possible implications for the male reproductive tract.
OBJECTIVE
The goal for the present study was to review the current status of the literature concerning COVID-19 and male reproduction.
MATERIAL AND METHODS
An electronic literature search was done by using PubMed and Google Scholar databases. Relevant papers, concerning SARS-COV-2 and COVID-19 and male reproduction, published between January 2020 and December 2020 were selected, analyzed and eventually included in the present literature review.
RESULTS
SARS-CoV-2 may infect any cell type expressing angiotensin-converting enzyme 2 (ACE2), including reproductive cells. Besides the presence of the SARS-CoV-2 receptor, the expression of host proteases, such as transmembrane serine protease 2 (TMPRSS2), is needed to cleave the viral S protein, allowing permanent fusion of the viral and host cell membranes. Here, we aimed to review the current status of the literature concerning COVID-19 and male reproduction. The lack of co-expression of ACE2 and TMPRSS2 in the testis suggests that sperm cells may not be at increased risk of viral entry and spread. However, the presence of orchitis in COVID-19-confirmed patients and compromised sex-related hormonal balance among these patients intrigues reproductive medicine.
DISCUSSION
SARS-CoV-2 may use alternate receptors to enter certain cell types, or the expression of ACE2 and TMPRSS2 may not be detected in healthy individuals.
CONCLUSION
COVID-19 challenges all medical areas, including reproductive medicine. It is not yet clear what effects, if any, the COVID-19 pandemic will have on male reproduction. Further research is needed to understand the long-term impact of SARS-CoV-2 on male reproductive function.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Genitalia, Male; Humans; Male; Reproduction
PubMed: 33998143
DOI: 10.1111/andr.13037 -
Ultrasonography (Seoul, Korea) Jul 2021The purpose of this pictorial essay is to describe the ultrasonographic and clinical findings of patients with small testes due to a wide range of causes. We...
The purpose of this pictorial essay is to describe the ultrasonographic and clinical findings of patients with small testes due to a wide range of causes. We retrospectively reviewed the ultrasonographic and clinical findings of various causes of small testes. We present various causes of small testes on ultrasonography including Klinefelter syndrome, testicular torsion, mumps orchitis, inguinal hernia, cryptorchidism, varicocele, and trauma. On ultrasonography, small testes in patients with testicular torsion, mumps orchitis, and trauma usually showed heterogeneous echogenicity. Atrophic testes were homogeneously hypoechoic in patients with cryptorchidism and inguinal hernia and were isoechoic to the normal testis in patients with varicocele. Klinefelter syndrome patients had small hyperechoic or hypoechoic nodules, but the echogenicity of the remnant portion of the testes was homogeneous. Ultrasonography is helpful for detecting small testes and for the differential diagnosis of the various possible causes of small testes.
PubMed: 33455146
DOI: 10.14366/usg.20133