Sodium-glucose cotransporter 2 inhibitor-associated severe epididymo-orchitis.

A man in his late 50s, with uncontrolled type 2 diabetes mellitus (T2DM) and morbid obesity, presented to the hospital with complicated epididymo-orchitis. The onset of symptoms (scrotal pain, erythema and swelling) occurred after the use of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, for 2 months. His baseline antidiabetic medications were insulin, glipizide and metformin. Initially, he had failed treatment of epididymo-orchitis with oral levofloxacin for 3 weeks, followed by 2 weeks of doxycycline therapy. At the presentation to the hospital, an ultrasound of the scrotum revealed scrotal and right testicular abscess. The patient underwent right inguinal orchiectomy. Postoperatively, pus culture was positive for Enterococcus faecalis and Candida glabrata, and hence, he was treated with oral antibiotics including high-dose antifungal medications. Adequate wound care and regular follow-up demonstrated resolution of infection. This case highlights the risk of severe urogenital infection associated with the use of SGLT2 inhibitors in the setting of uncontrolled T2DM.

Lipopolysaccharide-induced epididymitis modifies the transcriptional profile of Wfdc genes in mice†.

Whey-acidic protein four-disulfide core domain (WFDC) genes display putative roles in innate immunity and fertility. In mice, a locus on chromosome 2 contains 5 and 11 Wfdc genes in its centromeric and telomeric subloci, respectively. Although Wfdc genes are highly expressed in the epididymis, their contributions to epididymal function remain elusive. Here, we investigated whether Wfdc genes are regulated in response to lipopolysaccharide (LPS)-induced epididymitis, an inflammatory condition that impairs male fertility. We induced epididymitis in mice via (i) interstitial LPS injection into epididymal initial segment and (ii) intravasal LPS injection into the vas deferens towards cauda epididymis. Interstitial and intravasal LPS induced a differential upregulation of inflammatory mediators (interleukin 1 beta, interleukin 6, tumor necrosis factor, interferon gamma, and interleukin 10) in the initial segment and cauda epididymis within 72 h post-treatment. These changes were accompanied by a time-dependent endotoxin clearance from the epididymis. In the initial segment, interstitial LPS upregulated all centromeric (Slpi, Wfdc5, Wfdc12, Wfdc15a, and Wfdc15b) and five telomeric (Wfdc2, Wfdc3, Wfdc6b, Wfdc10, and Wfdc13) Wfdc transcripts at 24 and 72 h. In the cauda epididymis, intravasal LPS upregulated Wfdc5 and Wfdc2 transcripts at 24 h, followed by a downregulation of Wfdc15b and three telomeric (Wfdc6a, Wfdc11, and Wfdc16) gene transcripts at 72 h. Pharmacological inhibition of nuclear factor kappa B activation prevented LPS-induced upregulation of centromeric and telomeric Wfdc genes depending on the epididymal region. We show that LPS-induced inflammation differentially regulated the Wfdc locus in the proximal and distal epididymis, indicating region-specific roles for the Wfdc family in innate immune responses during epididymitis.

S100A4 promotes the progression of lipopolysaccharide-induced acute epididymitis in mice†.

S100A4 has been suggested to be a critical regulator of tumor metastasis and is implicated in the progression of inflammation. The aim of this study is to investigate the expression and possible role of S100A4 in epididymitis. Using a mouse model of epididymitis induced by the injection of lipopolysaccharide (LPS) in the deferent duct, we found that LPS administration induced an upregulation of S100a4 transcription (P < 0.05) and a recruitment of S100A4 positive cells in the epididymal interstitium of wild type (WT) mice. Co-immunofluorescence showed that S100A4 was mainly expressed by granulocytes, CD4 lymphocytes, and macrophages. Deficiency of S100A4 reduced epididymal pathological reaction and the mRNA levels of the pro-inflammatory cytokines IL-1ß and TNF-α (P < 0.01), suggesting that S100A4 promotes the progression of epididymitis. Furthermore, S100A4 deficiency alleviated the decline of sperm motility and rectified the abnormal expression of sperm membrane protein AMAD3, which suggested that in the progression of epididymitis, S100A4 aggravates the damage to sperm vitality. In addition, both Ki-67 marked cell proliferation and transferase-mediated dUTP-biotin nick end labeling detected cell apoptosis were reduced in S100a4-/- mice compared with WT mice after LPS treatment, indicating that S100A4 promotes both cell proliferation and cell apoptosis in epididymitis. Overall, these results demonstrate that S100A4 promotes the progression of LPS-induced epididymitis and facilitates a decline in sperm vitality, and its function may be related to the process of cell proliferation and apoptosis during inflammation.

A rare case of multi-focal human TB after BCG instillation for non-muscle-invasive bladder cancer.

OBJECTIVE: To describe a left epididymitis and para-aortical involvement caused by Mycobacterium tuberculosis hominis reactivation after bacillus Calmette-Guérin instillation for non-muscle-invasive bladder cancer. PATIENT AND METHODS: A Caucasian male, aged 76 years, exposed to bacillus Calmette-Guérin for a high-grade non-muscle-invasive bladder cancer in 2015, reported painful and progressive left scrotal swelling with purulent discharge from a cutaneous fistulous track that yielded, on liquid culture, a pan-susceptible Mycobacterium tuberculosis hominis strain. Moreover, after 6 months of anti-tuberculosis treatment, an abdominal peri-aortic mass, sized 4 cm, was found and a surgical biopsy showed necrotizing granulomas; however, although smear microscopy and Xpert MTB/Rif™ performed on fresh biopsy sample were positive, liquid cultures resulted negative, indicating treatment efficacy. RESULTS: Numerous peculiar and multi-organ involvement due to BCGitis after intravesical immunotherapy have been previously described, including 17 scientific articles about epididymitis, however, no reports so far showed reactivation of Mycobacterium tuberculosis hominis after bacillus Calmette-Guérin treatment. CONCLUSION: Although BCGitis is more prevalent in patients undergoing bacillus Calmette-Guérin instillation for non-muscle-invasive bladder cancer, tuberculosis by other species of Mycobacterium tuberculosis should be always ruled out by molecular and conventional microbiology in patients with a history of Mycobacterium tuberculosis hominis exposure.

Melatonin protects against lipopolysaccharide-induced epididymitis in sheep epididymal epithelial cells in vitro.

Melatonin has protective effects against inflammation but its role in epididymitis is unknown. We addressed this in the present study using lipopolysaccharide (LPS)-stimulated sheep epididymal epithelial cells as an in vitro inflammation model. We found that interleukin (IL)-1ß, IL-6, tumor necrosis factor α, and cyclooxygenase (COX)-2 mRNA levels; COX-2 and Toll-like receptor (TLR)-4 protein levels; and nuclear factor (NF)-κB p65 phosphorylation were increased by LPS treatment. These effects were reversed in a dose-dependent manner by melatonin (10-11-10-7 M). Quantitative reverse transcription PCR and immunofluorescence analyses showed that the melatonin receptors MT1 and MT2 were expressed in sheep epididymal epithelial cells. The inhibitory effect of melatonin on inflammation was abrogated by the MT1 and MT2 receptor antagonist luzindole and the MT2 ligand 4-phenyl-2-propanamide tetraldehyde. Thus, melatonin exerted anti-inflammatory effect in epididymal epithelial cells by inhibiting TLR4/NF-κB signaling, suggesting its potential as an effective drug for the treatment of epididymitis in sheep.

Comprehensive transcriptome analysis based on RNA sequencing identifies critical genes for lipopolysaccharide-induced epididymitis in a rat model.

Epididymitis is a commonly diagnosed disease associated with male infertility. However, little is known about the molecules that are involved in its development. This study was to identify critical genes associated with lipopolysaccharide-induced epididymitis and analyze the molecular mechanism of epididymitis through RNA sequencing. Experimental epididymitis models were generated by administering male Sprague-Dawley rats' lipopolysaccharide. A total of 1378 differentially expressed genes, including 531 upregulated and 847 downregulated genes, were identified in the epididymitis model rats compared with those in sham-operated rats by RNA sequencing. Functional enrichment analyses suggested that the upregulated genes were markedly enriched in inflammation-related biological processes, as well as in the tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interactions, complement and coagulation cascades, and in the chemokine signaling pathway. Four downregulated genes (collagen type XXVIII alpha 1 chain [Col28α1], cyclin-dependent kinase-like 1 [Cdkl1], phosphoserine phosphatase [Psph], and fatty acid desaturase 2 [Fads2]) and ten upregulated genes (CCAAT/enhancer-binding protein beta [Cebpß], C-X-C motif chemokine receptor 2 [Cxcr2], interleukin 11 [Il11], C-C motif chemokine ligand 20 [Ccl20], nuclear factor-kappa-B inhibitor alpha [Nfkbiα], claudin 4 [Cldn4], matrix metallopeptidase 9 [Mmp9], heat shock 70 kDa protein 8 [Hspa8], intercellular cell adhesion molecule-1 [Icam1], and Jun) were successfully confirmed by real-time polymerase chain reaction. Western blot demonstrated that CDKL1 was decreased, while MMP9 and NFKBIA were increased in the experimental model group compared with those in the sham-operated group. Our study sheds new light on the understanding of the early response of the epididymis during bacterial epididymitis.

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy.

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.

Lipopolysaccharide-induced testicular dysfunction and epididymitis in mice: a critical role of tumor necrosis factor alpha†.

Systemic inflammation may impair male fertility, and its underlying mechanisms remain poorly understood. The present study investigates the effect of lipopolysaccharide (LPS)-induced systemic inflammation on the testis and epididymis in mice. Intraperitoneal injection of LPS significantly impaired testicular functions, including testosterone production, spermatogenesis, and blood-testis barrier permeability. The epididymitis characterized by leukocyte infiltration and fibrosis was observed in the cauda epididymis after LPS injection. LPS-induced testicular dysfunction and epididymitis were abolished in tumor necrosis factor alpha (Tnfa) knockout mice. Pomalidomide, a TNFA inhibitor, blocked the detrimental effects of LPS on the testis and epididymis. The results indicate that LPS-induced systemic inflammation impairs male fertility through TNFA production, suggesting that the intervention on TNFA production would be considered for the prevention and treatment of inflammatory impairment of male fertility.

Juvenile allergic urethritis with urethro-ejaculatory reflux presenting as acute intermittent bilateral testicular torsion.

We report a case of juvenile allergic urethritis secondary to double concentrate orange squash of a famous brand in a 3-year-old boy who developed bilateral urethro-ejaculatory reflux (UER) and severe urethral, perineal and scrotal pain referred to both lower limbs intermittently predominantly during and after micturition-simulating features of bilateral intermittent testicular torsion. Accurate history, urinalysis, ultrasound, colour Doppler and food challenge were helpful in diagnosis. Topical steroids, antihistaminic, analgesic and anti-inflammatory medications together with withdrawal of the allergen produced complete recovery. Allergic urethritis in association with bilateral UER causing secondary seminal vesiculitis and epididymitis is rare. It presented as acute scrotum and responded to innovative treatment. Allergic disease can have a dramatic effect on a child's quality of life. This is the first documented case of allergic urethritis and associated UER presenting as juvenile acute scrotum. Steroids, antihistamines and anti-inflammatory agents together with avoidance of the allergen helped achieve recovery.

Primary cell cultures for understanding rat epididymal inflammation.

Treatment-induced epididymal inflammation and granuloma formation is only an occasional problem in preclinical drug development, but it can effectively terminate the development of that candidate molecule. Screening for backup molecules without that toxicity must be performed in animals (generally rats) that requires at least 2 to 3 weeks of in vivo exposure, a great deal of specially synthesized candidate compound, and histologic examination of the target tissues. We instead hypothesized that these treatments induced proinflammatory gene expression, and so used mixed-cell cultures from the rat epididymal tubule to monitor the induction of proinflammatory cytokines. Cells were exposed for 24 hr and then cytotoxicity was evaluated with the MTS assay and mRNA levels of Interleukin-6 (IL-6) and growth-related oncogene (GRO) were measured. We found that compounds that were more toxic in vivo stimulated a greater induction of IL-6 and GRO mRNA levels in vitro. By relating effective concentrations in vitro with the predicted C(eff), we could rank compounds by their propensity to induce inflammation in rats in vivo. This method allowed the identification of several compounds with very low inflammatory induction in vitro. When tested in rats, the compounds produced small degrees of inflammation at an acceptable margin (approximately 20×), and have progressed into further development.

Amiodarone-induced epididymitis: a pathologically confirmed case report and review of the literature.

We report a case of amiodarone-induced epididymitis and review the pertinent literature. This disease is currently a diagnosis of exclusion and is believed to be self-limiting. We found new evidence for the pathological diagnosis and identified amiodarone-like crystals in the epididymis as a pathological mechanism of this disease. This case also suggests that amiodarone-induced epididymitis is not self-limiting. Continued use of amiodarone according to the current guidelines led to a bilateral epididymectomy. We recommend withdrawal or reduction of amiodarone dosage immediately once the signs and symptoms of epididymitis present in this population of patients. When epididymitis does not seem to be caused by an infection or any other identifiable etiology, this should not be overlooked by the cardiologist, urologist or general practitioner. These findings and recommendations should help reduce the suffering of patients and improve their clinical outcomes.

Neonatal exposure to diethylstilbestrol causes granulomatous orchitis via epididymal inflammation.

Diethylstilbestrol (DES), an endocrine-disrupting chemical, is an infamous artificial estrogenic compound. Although neonatal exposure to DES has been shown to result in inflammation of the male reproductive system, it has not, to our knowledge, been reported to induce testicular inflammation. Here we report that neonatal exposure to DES caused granulomatous orchitis with spermatogenic disturbance in 4 of 17 ICR male mice at 12 weeks of age. In the animals with spermatogenic disturbance, we observed either seminiferous tubules containing only cells with Sertoli cell features (likely Sertoli cell syndrome), or tubule cells in maturation arrest that contained only spermatogonia and/or spermatocytes. Following neonatal DES exposure, 5-week-old mice exhibited inflammation in cauda epididymis; by 8 weeks, the inflammation had spread to all segments of epididymis but not the testis; by 12 weeks, inflammation of the epididymis was observed in all mice. These data indicated that cauda epididymis has increased sensitivity to neonatal DES exposure compared to other segments of epididymis and testis. The data also implied that neonatal DES exposure-induced inflammation in cauda epididymis extended gradually to the testis via corpus and caput during development.

BCG intravesical: manejo práctico de sus efectos adversos / Intravesical BCG: practical management of its adverse effects

La inmunoterapia con instilación intravesical de bacilo Calmette-Guerin (BCG) es un tratamiento tópico vesical aceptado frente al cáncer de urotelio superficial de alto grado. Los efectosadversos de la BCG intravesical pueden ser locales y sistémicos. El problema más común es el síndrome miccional irritativo, por lo general autolimitado. Otras complicaciones locales son hematuria y retracción vesical. El aparato urinario puede afectarse en forma de nefritis,absceso renal, prostatitis, orqui-epididimitis y ulceración peneana. Las manifestaciones generales aparecen de forma precoz y consisten en un cuadro pseudogripal (fiebre, escalofríos,artralgias y afectación del estado general) que se autolimita en pocos días. Los cuadros más graves de toxicidad sistémica incluyen septicemia y fallo multiorgánico. La hepatitis y la neumonitisgranulomatosa de deben a la infección tuberculosa. La afectación inflamatoria visceral y las artralgias se deben a la reacción de hipersensibilidad. Las complicaciones osteo-articularescomo espondilitis, osteomielitis vertebral y artritis pueden ser asimismo infecciosaso reactivas. En el plano dermatológico lo más común en la aparición de púrpura . Cualquiera de las complicaciones graves contraindica seguir la inmunoterapia con BCG. Las reacciones de hipersensibilidad se tratan con corticoterapia, mientras que las complicaciones sépticas precisan tuberculostáticos. Se realiza una revisión de las complicaciones de la BCG y de suabordaje diagnóstico y terapéutico desde un punto de vista práctico (AU)

Immunotherapy with Calmette-Guerin bacillus intravesical instillation (BCG) is the gold standard treatment against high grade urothelial cancer of the bladder. The adverse effects of intravesical BCG may be local or systemic. Irritative voiding symptoms, usually self-limited is the most common problem. Hematuria and bladder retraction are other local complications. Urinary system and genitalia may be affected as a nephritis, renal abscess, prostatitis, epididymo- orchitis and penile ulceration. The general symptoms appear early as flu-like illness (fever, chills, arthralgia, and malaise) that limits itself within days. The most severe systemic toxicity included sepsis and multiorgan failure. Granulomatous hepatitis and pneumonitis are due to tuberculous infection. Inflammatory visceral involvement and arthralgias are due to hypersensitivity reaction. Osteoarticular complications such as spondylitis, vertebral osteomyelitis and arthritis can be infectious or reactive. The most common dermatological undesirable effect is purpura. Any further serious complications contraindicate immunotherapy with BCG. Hipersensitibity reactions are treated with steroids, while septic complications requiring tuberculostatic therapy. We present a brew review of the complications of BCG and its diagnostic and therapeutic approach from a practical standpoint (AU)

Amiodarone-induced epididymitis: a case report and review of the literature.

Epididymitis, as an unusual side-effect of amiodarone use, in a patient with dilated cardiomyopathy is reported along with a pertinent literature review. The diagnosis was one of exclusion after the patient received several regimens of antimicrobials and was only established after a dose reduction of the amiodarone regimen. Cardiologists should be aware of this rare but existing side effect of amiodarone, in order promptly intervene with dose adjustment or discontinuation of amiodarone and to avoid prolonged use of unnecessary antimicrobial regimens.

[Tuberculous epididymitis caused by intravesical BCG therapy: a case report].

We describe a case of tuberculous epididymitis that occurred 35 months after completion of a course of intravesical Bacillus Calmette-Guerin (BCG). A 67-year-old man had received trasuretheral resection for bladder cancer in February 1997. Two weeks after the operation, a course of 8 weekly intravesical instillations of BCG (Tokyo 172 strain) was carried out between March and April, 1997. Under the diagnosis of benign prostatic hypertrophy, transuretheral resection of the prostate was performed in March 1998. Multiple tuberculous nodules were histopathologically detected in resected prostatic tissues. The patient complained of a small nodule in the right epididymal tail in August 2001. The nodule developed during 6 weeks, with spontaneous perforation of the scrotal skin and discharge of pus. The pus contained acid-fast bacilli, which were shown to be tubercle bacilli by polymerase chain reaction (PCR) with pan-mycobacterium primer. MPB64-T2, T6 and pncA-7, 11C were positive, while PT-1, 2 and pncA-7, 10 were negative by PCR. These results revealed that Mycobacterium bovis (BCG Organism) was the cause of the epididymitis. Drug therapy for 3 months with rifampicin, isoniazid and ethambutol was initiated in September 2001, and right orchiectomy was performed in October. Histopathological examination showed tuberculous epididymitis. In this case, persistent BCG organisms may have reached the epididymis from the prostate, and may have been activated by immunosuppression associated with aging. In addition, PCR with species-specific primers was useful in differentiating Mycobacterium bovis from Mycobacterium tuberculosis.

Urologic complications of nonurologic medications.

A physician must be aware of common drug side effects and interactions before prescribing a certain agent. In addition to the drugs that we, as urologists, prescribe, we must also be aware of the urologic side effects of drugs that are commonly prescribed by nonurologists. The mechanisms of the pharmacologic causes for voiding dysfunction, erectile and sexual dysfunction, infertility, and urolithiasis are often mutifactorial and incompletely understood. The recognition and association of a particular drug's potential side effects may save valuable time and money involved in the workup of a patient with a new urologic complaint. It is incumbent on the practicing urologist to be able to recognize the common, and sometimes subtle, urologic complications of medications that are used for nonurologic conditions.

Epididymo-orchitis following intravesical bacillus Calmette-Guérin therapy.

OBJECTIVE: To describe a case of epididymo-orchitis that developed four years after treatment with intravesical bacillus Calmette-Guérin (BCG) and to review the incidence of this adverse effect. DATA SOURCES: Information about the patient was obtained from the medical chart. A MEDLINE search of English-language literature (from January 1976 to April 1999) was conducted. STUDY SELECTION: All case reports of BCG-related epididymo-orchitis were evaluated. Review articles describing complications of BCG therapy for bladder cancer and the prevention and treatment of these complications were reviewed. DATA EXTRACTION: Studies were evaluated for reports of BCG-related epididymo-orchitis and its treatment. DATA SYNTHESIS: Our case report is compared with others reported in the literature. The incidence of BCG-associated epididymoorchitis is rare. CONCLUSIONS: Epididymo-orchitis should be considered as a late complication of BCG therapy for bladder cancer. Proper patient selection may help decrease the risk of complications from BCG therapy.

Amiodarone induced epididymitis in children.

PURPOSE: Amiodarone is an antiarrythmic agent, which is often successfully used when all other antiarrythmics have failed. Sterile epididymitis is a recognized complication of treatment in adults, occurring in up to 11% of patients. To date there have been no reported cases of amiodarone induced epididymitis in children. We present a previously unrecognized cause of epididymitis in boys. MATERIALS AND METHODS: The medical records, including radiographic imaging, pathology and operative reports, of 2 postpubertal boys who had sterile epididymitis after prolonged therapy with amiodarone were reviewed. RESULTS: In both cases the onset of scrotal pain and subsequent evaluation led to diagnosis of epidydimitis. Amiodarone was determined to be the cause, and cessation of the drug resulted in symptom resolution in 1 case. CONCLUSIONS: While it remains uncertain, the pathophysiology of amiodarone induced epididymitis is likely related to its high concentration in testicular tissue. Recognition that amiodarone is a rare but significant cause of epididymitis in children is important to prevent unnecessary surgery in high risk patients. Amiodarone induced epididymitis in children tends to be a self-limited process and of secondary importance to the serious cardiac disease. Whereas discontinuing amiodarone risks sudden cardiac death, a reduction in dosage or temporary cessation of the drug may result in rapid resolution of the epididymitis.