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Journal of Andrology 2011The ability of spermatogenic cells to evade the host immune system and the ability of systemic inflammation to inhibit male reproductive function represent two of the... (Review)
Review
The ability of spermatogenic cells to evade the host immune system and the ability of systemic inflammation to inhibit male reproductive function represent two of the most intriguing conundrums of male reproduction. Clearly, an understanding of the underlying immunology of the male reproductive tract is crucial to resolving these superficially incompatible observations. One important consideration must be the very different immunological environments of the testis, where sperm develop, and the epididymis, where sperm mature and are stored. Compared with the elaborate blood-testis barrier, the tight junctions of the epididymis are much less effective. Unlike the seminiferous epithelium, immune cells are commonly observed within the epithelium, and can even be found within the lumen, of the epididymis. Crucially, there is little evidence for extended allograft survival (immune privilege) in the epididymis, as it exists in the testis, and the epididymis is much more susceptible to loss of immune tolerance. Moreover, the incidence of epididymitis is considerably greater than that of orchitis in humans, and susceptibility to sperm antibody formation after damage to the epididymis or vas deferens increases with increasing distance of the damage from the testis. Although we still know relatively little about testicular immunity, we know less about the interactions between the epididymis and the immune system. Given that the epididymis appears to be more susceptible to inflammation and immune reactions than the testis, and thereby represents the weaker link in protecting developing sperm from the immune system, it is probably time this imbalance in knowledge was addressed.
Topics: Animals; Bacterial Infections; Blood-Testis Barrier; Epididymis; Epididymitis; Humans; Immune Tolerance; Immunity, Cellular; Immunity, Innate; Male; Mice; Orchitis; Rats; Testis; Vas Deferens; Virus Diseases
PubMed: 21764900
DOI: 10.2164/jandrol.111.012989 -
The Oncologist Jul 2019Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma,...
BACKGROUND
Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life-threatening immune-related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies.
CASE PRESENTATION
We describe herein a patient with metastatic melanoma who developed epididymo-orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo-orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad-spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next-generation sequencing assay, was negative. He received high-dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5-week taper of oral steroids.
DISCUSSION
Here, we report a case of epididymo-orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents.
KEY POINTS
Epididymo-orchitis is a rare and potentially life-threatening complication of anti-programmed death protein 1 (anti-PD-1) therapy.For patients on anti-PD-1 therapy who develop either epididymo-orchitis or epididymitis without clear infectious cause, immune-related adverse events should be considered in the differential diagnosis.If severe, epididymo-orchitis related to anti-PD-1 therapy may be treated with high-dose corticosteroids.
Topics: Adrenal Cortex Hormones; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Encephalitis; Epididymitis; Humans; Male; Melanoma; Orchitis; Prognosis; Programmed Cell Death 1 Receptor; Uveal Neoplasms
PubMed: 30936376
DOI: 10.1634/theoncologist.2018-0722 -
European Journal of Case Reports in... 2024Epididymitis is a common cause of scrotal pain in adults, with coliform bacteria being the most common isolated organisms in patients older than 35.
BACKGROUND
Epididymitis is a common cause of scrotal pain in adults, with coliform bacteria being the most common isolated organisms in patients older than 35.
CASE PRESENTATION
A 51-year-old healthy patient presented with scrotal pain and swelling, and was found to have epididymo-orchitis and bacteraemia caused by , which has not previously been reported as a cause of epididymo-orchitis and bacteraemia in immunocompetent patients.
DISCUSSION
Diagnostic studies can help confirm the diagnosis and detect the causative pathogen. In all suspected cases, a urinalysis, urine culture and a urine or urethral swab for nucleic acid amplification tests (NAATs) for and should be performed. Colour Doppler ultrasonography often shows an enlarged thickened epididymis with increased Doppler wave pulsation in epididymitis. are pleomorphic gram-negative rods that commonly colonise the human respiratory tract and are associated with a number of clinical conditions. has been reported as a cause of epididymo-orchitis in prepubertal boys, and in few cases were associated with positive blood cultures. In adults, has been isolated before from urine samples or urethral swabs in patients with epididymitis or epididymo-orchitis.
CONCLUSION
This case highlights the possibility of causing epididymo-orchitis and bacteraemia in immunocompetent patients. Healthcare providers should consider in the differential diagnosis of epididymitis and epididymo-orchitis in both immunocompetent and immunocompromised patients.
LEARNING POINTS
can cause epididymo-orchitis and bacteraemia in immunocompetent patients. This has not been previously reported. should be considered in the differential diagnosis of epididymitis and epididymo-orchitis in both immunocompromised and immunocompetent patients.Healthcare providers should be aware of the increasing incidence of epididymitis and epididymo-orchitis caused by non-coliform bacteria in patients older than 35 years, especially in immunocompromised patients.
PubMed: 38223271
DOI: 10.12890/2023_004205 -
British Medical Journal Feb 1973
Topics: Abdomen; Adult; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Male; Meningitis, Viral; Mumps; Orchitis; Pain; Pregnancy
PubMed: 4685627
DOI: 10.1136/bmj.1.5849.338 -
Human Reproduction Update Jul 2018Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or... (Review)
Review
BACKGROUND
Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans.
OBJECTIVE AND RATIONALE
This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions.
SEARCH METHODS
An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: 'infection' and/or 'inflammation' and 'testis' and/or 'epididymis', 'infection' and/or 'inflammation' and 'male genital tract', 'male infertility', 'orchitis', 'epididymitis', 'experimental autoimmune' and 'orchitis' or 'epididymitis' or 'epididymo-orchitis', antisperm antibodies', 'vasectomy'. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team.
OUTCOMES
There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with 'mixed atrophy' of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response.
WIDER IMPLICATIONS
This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Humans; Infections; Infertility, Male; Inflammation; Male; Orchitis; Rodentia
PubMed: 29648649
DOI: 10.1093/humupd/dmy009 -
Andrology Jan 2022Multi-organ damage is a common feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, going beyond the initially observed severe pneumonia....
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.
Topics: Adult; Aged; Aged, 80 and over; Autopsy; COVID-19; Humans; Male; Middle Aged; Orchitis; SARS-CoV-2; Testis
PubMed: 34196475
DOI: 10.1111/andr.13073 -
Indian Pediatrics May 2015
Topics: Humans; Ileum; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Atresia; Male; Meconium; Orchitis; Scrotum
PubMed: 26061946
DOI: 10.1007/s13312-015-0655-5 -
International Journal of Surgery Case... Jun 2021Acute scrotum is considered a urological emergency requiring early intervention depending on the cause. There are multiple causes of acute scrotum with testicular...
INTRODUCTION AND IMPORTANCE
Acute scrotum is considered a urological emergency requiring early intervention depending on the cause. There are multiple causes of acute scrotum with testicular torsion being the most feared as delayed treatment leads to testicular loss. However, differentiating between epididymo-orchitis and torsion can be very difficult.
CASE PRESENTATION
We present a case of an 18-year old male patient with 2 separate episodes of acute scrotum. He had epididymo-orchitis as the first presentation followed by testicular torsion 5 days later. To our knowledge this is the first case of testicular torsion secondary to epididymo-orchitis.
CLINICAL DISCUSSION
Differentiating between epididymo-orchitis and torsion is challenging but important due to risk of loss of testis with a wrong diagnosis. Once you establish epididymo-orchitis the suspicion for subsequent torsion should be high with close follow up and adequate counselling.
CONCLUSION
He ultimately had orchiectomy, although a rare presentation, enlarged testis due to epididymo-orchitis can predispose an individual to developing testicular torsion thus adequate counselling on warning signs to patients with epididymo-orchitis is of particular importance so as to intervene early and ultimately save the testis.
PubMed: 34062357
DOI: 10.1016/j.ijscr.2021.106038 -
Frontiers in Cell and Developmental... 2021Octamer-binding transcription factor 4 (OCT4) and cancerous inhibitor of protein phosphatase 2A (CIP2A) are upregulated in testicular cancer and cell lines. However, its...
Octamer-binding transcription factor 4 (OCT4) and cancerous inhibitor of protein phosphatase 2A (CIP2A) are upregulated in testicular cancer and cell lines. However, its contribution to orchitis (testicular inflammation) is unclear and was thus, investigated herein. Cell-based experiments on a lipopolysaccharide (LPS)-induced orchitis mouse model revealed robust inflammation, apoptotic cell death, and redox disorder in the Leydig (interstitial), Sertoli (supporting), and, germ cells. Meanwhile, real-time quantitative PCR revealed low OCT4 and CIP2A levels in testicular tissue and LPS-stimulated cells. A gain-of-function study showed that OCT4 overexpression not only increased CIP2A expression but also repressed LPS-induced inflammation, apoptosis, and redox disorder in the aforementioned cells. Furthermore, the re-inhibition of CIP2A expression by TD-19 in OCT4-overexpressing cells counteracted the effects of OCT4 overexpression on inflammation, apoptosis, and redox equilibrium. In addition, our results indicated that the Keap1-Nrf2-HO-1 signaling pathway was mediated by OCT4 and CIP2A. These findings provide insights into the potential mechanism underlying OCT4- and CIP2A-mediated testicular inflammation.
PubMed: 34513828
DOI: 10.3389/fcell.2021.683209 -
Reproductive Biology and Endocrinology... Mar 2004This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the mammalian testis and in two testicular pathologies, testicular torsion and orchitis. TNF... (Review)
Review
This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the mammalian testis and in two testicular pathologies, testicular torsion and orchitis. TNF alpha in the testis is produced by round spermatids, pachytene spermatocytes, and testicular macrophages. The type 1 TNF receptor has been found on Sertoli and Leydig cells and numerous studies suggest a paracrine mode of action for TNF alpha in the normal testis. IL-1 alpha has been reported to be produced by Sertoli cells, testicular macrophages, and possibly postmeiotic germ cells. IL-1 receptors have been reported on Sertoli cells, Leydig cells, testicular macrophages, and germ cells suggesting both autocrine and paracrine functions. While these proinflammatory cytokines have important roles in normal testicular homeostasis, an elevation of their expression can lead to testicular dysfunctions. Testicular torsion is a clinical pathology with results in testicular ischemia and surgical intervention is often required for reperfusion. A pivotal role for IL-1beta in the pathology of testicular torsion has been recently described whereby an increase in IL-1beta production after reperfusion of the testis is correlated with the activation of the stress-related kinase, c-jun N-terminal kinase, and ultimately resulting in neutrophil recruitment to the testis and germ cell apoptosis. In autoimmune orchitis, on the other hand, TNF alpha produced by T-lymphocytes and macrophages of the testis has been implicated in the development and progression of the disease. Thus, both proinflammatory cytokines, TNF alpha and IL-1, have significant roles in normal testicular functions as well as in certain testicular pathologies.
Topics: Animals; Autoimmune Diseases; Humans; Interleukin-1; Male; Mammals; Orchitis; Spermatic Cord Torsion; Testis; Tumor Necrosis Factor-alpha
PubMed: 15012831
DOI: 10.1186/1477-7827-2-9