Testicular torsion: its effect on autoimmunisation, pituitary-testis axis and correlation with primary gonadal dysfunction in boys.

BACKGROUND: Torsion of the testis is an urgent surgical condition that endangers the viability of the gonad and the fertility of the patient. Our aim was to assess potential autoimmune processes and hormonal abnormalities in boys operated on due to that illness. METHODS: The authors evaluated the levels of antibodies against sperm and Leydig cells, concentrations of follicle-stimulating, luteinizing and anti-Müllerian hormone, testosterone, oestradiol and vascular endothelial growth factor in the serum in 28 boys operated on due to torsion of the testis. Patients' sexual maturity was assessed according the Tanner scale (group G1, G4 and G5). RESULTS: No antibodies against sperm or Leydig cells were found in the serum. Statistically significant differences in follicle-stimulating and anti-Müllerian hormone concentrations were observed in the G1, and they were higher in the study than in the control group. There were no statistically significant differences in luteinizing hormone, testosterone, oestradiol and vascular endothelial growth factor concentrations in the study group or control group. Testosterone concentration was unrelated to total testicular volume. CONCLUSIONS: Results did not confirm the autoimmune process in boys with torsion of the testis. The pituitary-testis axis seems to have sufficient compensation capabilities. However, study results suggest that primary gonadal dysfunction may predispose to torsion. IMPACT: Significant differences exist between the literature data and own results on the formation of antibodies and hormonal changes due to testicular torsion in boys. It is a novel, prospective study on antibodies against sperms and Leydig cells in the serum and on hormonal processes occurring as a result of the testicular torsion from the prenatal period to the adolescence with division into pubertal groups. The study has revealed sufficient compensation capabilities of the pituitary-testis axis and no autoimmune process in boys with torsion of the testis.

Effect of ketotifen fumarate on experimental autoimmune orchitis and torsion of the spermatic cord.

The aim of this work was to study effects of ketotifen fumarate (KF) on prevention of tissue damage in testes of rats with experimental autoimmune orchitis (EAO) and on the contralateral testis in a model of prolonged testicular cord torsion (TCT). Rats with EAO or TCT were injected intraperitoneally once daily with KF or saline solution (vehicle group). Incidence and severity of testicular damage were evaluated by histopathology using an EAO score or a Johnsen score. Mast cells (MC) were identified by histochemistry and quantified. In EAO model, KF significantly reduced severity of histopathological testicular damage compared to rats in the vehicle group. KF also reduced the number of testicular MC compared to vehicle group. Similarly, in TCT model, multifocal damage of the contralateral testis was observed 30 days after testicular torsion characterized by sloughing of the germinal epithelium, seminiferous tubule atrophy, and interstitial edema. Focal signs of inflammation and fibrosis of seminiferous tubular walls were also observed. In contrast, sections of contralateral testis of rats injected with KF and killed 30 days after surgery showed normal histological features. A significant decrease in the number of MC was observed in rats treated with KF compared to untreated animals. In conclusion, we demonstrated that treatment with KF reduced testicular inflammatory process and MC infiltrates in both EAO and TCT models. The results suggest a promising treatment for infertile male patients with testicular pathologies associated with inflammation and germ cell loss.

Immunological effects of acute testicular torsion on the contralateral testis in rats.

AIM: The mechanism by which unilateral testicular torsion leads to injury of the contralateral testis is still controversial. The present study aimed to evaluate immunohistopathological changes in the contralateral testis of rats after acute testicular torsion. METHODS: 40 pubertal rats were randomly divided into 3 groups. Group 1 (n=10) functioned as controls. Group 2 rats (n=10) underwent a sham operation, and Group 3 (n=20) underwent 720° torsion of the left spermatic cord (3 h) followed by detorsion (24 h). RESULTS: Immunofluorescence tests were done to investigate contralateral lesions in half of the animals in Group 3. Nitro blue tetrazolium (NBT) was injected in both testes to identify the presence of oxygen-derived free radicals. 24 h after reperfusion, bilateral samples of the testes were obtained for histological analysis. Fisher's exact test was used for statistical analysis with p-values <0.05 considered significant.Immunofluorescence tests were positive for the contralateral (right) testis but with a lower intensity than that of the testis submitted to torsion. NBT reaction was intense all over the left testis while a minor reaction was visible in the right testis. In Group 3 the left distorted testicle showed diffuse edema with cell elimination and extensive necrosis of the seminiferous tubules. Histological lesions were moderate to mild in the contralateral testis. CONCLUSION: An autoimmune IgG-mediated mechanism deposited on the basement membrane of seminiferous tubules seems to be involved in the genesis of contralateral testis injury.

[Testicular perfusion injury. Cytokines and cell adhesion molecules in humans]. / Testikuläre Ischämie. Verlauf von Zytokinen und Zelladhäsionsmolekülen beim Menschen.

BACKGROUND: Ischemia and reperfusion (I/R) lead to cellular damage. A disturbance of testicular perfusion occurs during the therapy of cryptorchidism and in cases of testicular torsion. This results in the activation of mediator cells with an increasing synthesis of mediators of infection like TNF-alpha and the expression of cell adhesion molecules like ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) at the cellular surface. METHODS: The expression of the cytokines IL-10 and TNF-alpha and the adhesion molecules ICAM and VCAM after defined testicular I/R injury in nine male transsexuals was evaluated with rt-PCR. Furthermore we examined lactate and the diameter of the testicular tubulus under ischemic conditions. RESULTS: During ischemia ICAM, IL-10, and VCAM do not show significant changes on the side of testicular ischemia and the contralateral side; the same was seen for the tubulus diameter. TNF-alpha and the testicular lactate values showed a significant change of the expression pattern. DISCUSSION: The statistical changes of TNF-alpha and testicular lactate are the expression of leukocyte migration, infectious reaction, and immune response. To what extent the TNF-alpha expression represents a severe immunological reaction remains undefined. This human study shows primary results for the immunological understanding of and cellular response to testicular ischemia.

Late hormonal levels, semen parameters, and presence of antisperm antibodies in patients treated for testicular torsion.

In spite of prompt diagnosis and either orchiectomy or preservation of the affected testis, infertility remains a significant sequel to testicular torsion. The objective of this study was to evaluate the late endocrine profile, seminal parameters, and antisperm antibody levels after testicular torsion. We also analyzed the impact of orchiectomy or detorsion on the organ fate. Of 24 patients evaluated after testicular torsion, 15 were treated with orchiectomy (group 1) and 9 were treated with orchiopexy (group 2). All subjects were assessed by semen analysis, endocrine profile (levels of follicle-stimulating hormone, luteinizing hormone, and testosterone), and seminal antisperm antibody levels. A group of 20 proven fertile men was used as the control. Median ischemia time in group 1 (48 hours) was significantly higher than in group 2 (7 hours). Both groups demonstrated decreases in sperm count and morphology compared with controls. Group 1 showed a significantly higher motility than group 2 (P = .02). Group 1 also showed a significantly better morphology by World Health Organization and Kruger criteria than group 2 (P = .01). All patients presented endocrine profiles within the normal range, and no significant differences in antisperm antibody levels were detected between the groups. However, a trend for higher levels was found in patients treated for testicular torsion, regardless of the fate of the testis. Moreover, no significant correlation was found between antisperm antibody levels and age at torsion, ischemia time, seminal parameters, or treatment applied. In conclusion, we found that after torsion patients maintain late hormonal levels within the normal range. Testicular fate did not have any correlation with the formation of antisperm antibodies. Although sperm quality was preserved in most of the patients with the exception of sperm morphology, patients treated with orchiectomy presented better motility and morphology compared with the detorsion group. Further studies may clarify whether maintenance of a severely ischemic testicle may impair testicular function.

[Antisperm-antibodies induced by testicular torsion and its influence on testicular function].

OBJECTIVE: To investigate the changes of antisperm antibodies (AsAb), sexual hormones, and inhibin B (INH B) in patients before and after testicular torsion, as well as the effects of these factors on testicular function and reproduction. METHODS: Ten patients with single acute testicular torsion (left side 9 and right side 1), aged 16-45 years (19.6 on average), disease course of 3-6 days (averaging 4.7 days), underwent surgical removal of the damaged testis. Before and after the operation, serum AsAb (IgG, IgM, IgA) and INH B were measured by ELISA, and serum follicle-stimulating hormone (FSH), luteotropic hormone (LH), and testosterone (T) determined by chemoluminescence autoanalyzer. RESULTS: After the operation, the AsAb levels rose significantly and remained high for at least 26 weeks. The level of INH B was the lowest in the 3rd week and restored to normal in the 12th week, with significant difference between preoperation and the 3rd or the 6th week after the operation. The levels of LH and INH B in the 26th week were elevated significantly compared with the 6th. CONCLUSION: Testicular injury induced the elevation of AsAb, which would last a very long time. The change of INH B was closely related with the injury of the testis, which reflected the degree of testicular injury and functional restoration of the patients after the operation. Our study showed that AsAb and INH B can be used as useful tools for monitoring testicular function and reproduction.

[Long-term and late results of treatment in patients with a history of testicular torsion]. / Odlegle i pózne wyniki leczenia chorych z przebytym skretem jadra.

Testicular torsion is a surgical urgency. It may lead to loss of that organ and moreover, as revealed by experimental studies and clinical findings in adults, induces autoimmunological reactions with subsequent male infertility. To elucidate these sequellae the following questions seem to be relevant 1. Are there any antisperm antibodies or shifts in T cell CD4+, CD8+ and NK subpopulations in boys with a history of testicular torsion? 2. Is production of antisperm antibodies initiated and maintained in childhood, and amplified after puberty? 3. Does the age at testicular torsion and duration of exposure to sperm antigens/testicular tissue have an effect on induction and levels of antisperm antibodies? 4. Is hormonal function of testis/testes and gonadotropic activity of the pituitary gland normal in these patients? 5. What conditions (duration, subjective and objective symptoms) are associated with testicular torsion; what kind of intraoperative findings can be expected; what is the influence of testicular torsion on the twisted testis? The study group (GB) consisted of 37 boys and men aged from 8 months to 27 years (mean 12.3 years) recruited from 86 patients seen for testicular torsion at the Department of Pediatric Surgery, Pomeranian Academy of Medicine in Szczecin, between 1967 and 1992. The control group (GK) comprised 42 healthy boys and men aged 3 to 33 years (mean 12.1 years) (Tab. 1). The analysis was based on: 1) clinical files; 2) follow-up results; 3) laboratory findings; 4) statistics. According to clinical data and physical examination, testicular torsion usually appeared during puberty, neonatal period and infancy and the mean duration of torsion was 12.4 days. The best prognosis for salvage of the twisted testis was for torsions lasting no longer than 8 hours. Only 8 of 37 twisted testes could be salvaged (including 4 hypotrophic testes; Tab. 2). There were 21 positive ELISA tests (level of antisperm antibodies exceeding 2 fg/pl) in the study group (mean 4.45 +/- 5.6 fg/pl), including 13 boys with testicular torsion in the prepubertal age and 8 during puberty (Tab. 3). A tendency to higher levels of antibodies with age was observed. In the control group there were 35 negative and 7 positive results (mean 1.05 +/- 1.86 fg/pl) (Tab. 4), significantly less than in the study group (p < 0.001). Trend curves (Fig. 1) and Pearson's correlation coefficients (Fig. 2) for levels of antibodies and age at presentation of testicular torsion were established for both groups. Mean percentages of CD4+, CD8+ and NK cells (indirect immunofluorescence test with monoclonal antibodies) were insignificantly lower in the study group (Fig. 3). Shifts in favor of CD4+ and NK subpopulations found in some patients correlated with high levels of antisperm antibodies (Tab. 5 and Fig. 4). Elevated LH and/or FSH (21 patients) and/or testosterone levels (13 patients) were usually observed during puberty (Tab. 6). The results indicate that antisperm antibodies are detected in more than half of the boys with a history of testicular torsion. This is accompanied in some cases by shifts in CD4+ and NK lymphocyte subpopulations correlating with high antibody levels. Production of antisperm antibodies initiated during prepuberty (in infancy or even in the neonatal period) persists and is amplified after puberty due to increasing amounts of antigen material. Age at testicular torsion (age at potential exposure to spermatic antigens/testicular tissue from the twisted or de-twisted testis with severe haemorrhagic lesions or left in the abdominal cavity) has an effect on the future production and levels of antisperm antibodies. Disturbances in the secretion of LH and/or FSH were observed in 2/3 of the boys/men with a history of testicular torsion. Abnormal secretion of testosterone was found in 1/3 of the patients. These hormonal disorders seem to have no influence on virilization, libido or sexual potency.

Immunologic aspect of testicular torsion: detection of antisperm antibodies in contralateral testicle.

OBJECTIVE: To evaluate the immunologic etiology in unilateral testicular torsion, an experimental study in rats was carried out. MATERIALS AND METHODS: 75 adult Wistar rats included in the study program were divided into six different groups according to a torsion-detorsion procedure. Torsion degree was kept constant for all animals (720 degrees ). Anti-rat immunoglobulin G (IgG) antibodies against spermatozoa antigens were identified in contralateral testicular tissue after 1 month following detorsion and/or orchiectomy of the twisted testicle. RESULTS: We revealed antibody formation in animals subjected to unilateral torsion for 12 and 24 h, which then followed by detorsion of the testicle. IgG was identified especially on basal membrane of the tubules. CONCLUSIONS: As the controversy on the exact mechanism of testicular damage in unilateral torsion still continues, our findings showed that a possible immunological etiology may play an important role in this respect.

Aspectos imunológicos da torçäo testicular: trabalho experimental em ratos / Immunologic aspects of testicular torsion: experimental study in wistar rats

As atividades testiculares, hormonal e espermiogênica säo de extrema importância para o homem e para a manutençäo e o aprimoramento da humanidade. Trauma, tumores, varicocle, criptorquidia, anorquia, atrofias, torçäo de cordäo espermático, estäo entre as diversas causas da infertilidade masculina. A integridade da barreira testículo - sangüínea parece ter um papel fundamental na patôgenese da orquite auto-imune. A orquite auto-imune é um processo inflamatório testicular mediado por formaçäo de anticorpos, contra os próprios antígenos testiculares do indivíduo, causando lesöes no epitélio germinativo. Neste estudo foram utilizados oitenta (80) ratos Wistar, singênicos, machos, adultos, separados em dez grupos, submetidos à torçäo unilateral do testículo, sob anestesia, por um período de duas à doze horas, seguido, entäo, de destorçäo e exame anatomopatológico das gônadas contralateral e ipsilateral, em períodos que variaram de duas à dez semanas. Estes testículos foram analisados através das técnicas de histologia e de imunofluorescência com a utilizaçäo de anticorpos monoclonais para as imunoglobulinas IgA, IgG e IgM de coelho e cabra, contra os antígenos testiculares do rato, para que se estudasse as possíveis alteraçöes no tecido testicular do animal, objetivando a comprovaçäo da existência de complexos auto-imunes no epitélio germinal. O estudo demonstrou a presença de imunoglobulinas, principalmente das classes IgG e IgM na luza e no interstício dos túbulos semíferos. Alteraçöes estruturais do testículo contralateral, näo torcido, foram demonstradas. Os resultados deste experimento indicam que o sistema inume de animais sadios contém linfócitos com receptores para os próprios antígenos, capazes de, na torçäo unilateral do cordäo espermático, promoverem uma doença auto-imune. A utilizaçäo de substâncias imuno-supressoras, neste estudo, o corticóide, foi feita para tentar minimizar ou mesmo coibir o processo auto-agressivo. Existiu uma proteçäo testicular contralateral efetiva, com o uso precoce da referida droga. É sugerido que a permanência de um testículo necrótico na bolsa escrotal, após torçäo prolongada, pode levar à subfertilidade ou infertilidade.

[Immunologic response to testicular torsion. Experimental study on rats]. / Respuesta inmunológica a la torsión testicular. Trabajo experimental en ratas.

Men with a background of unilateral torsion of testis (t.t.) show a greater percentage of infertility and changes in the spermiogram. Currently, the cause of contralateral testicle affectation remains unknown. With the aim of verify whether these changes are secondary to an immunological mechanism, the authors conducted experimental work in 3 groups of male rats, inducing a right t.t. over 24 hours, followed by detorsion and preservation of contorted testicle. Immunological response is determined through direct and indirect immunofluorescence reactions, including a brief description of the technique used. Positive reactions were obtained in both the spermatozoa's head and flagellum, more frequently in animals killed at 30 days and gradually decreasing in those killed at 60 and 90 days. The authors compare their results to other experimental works, and recommend to perform orchiectomy because of the damaging effect of the contorted testicle over the contralateral one.

Late gonadal function and autoimmunization in familial testicular torsion.

Testicular torsion, one of the most common pediatric urological emergencies, is rarely familial. This study deals with the sixth recorded family with familial testicular torsion and the effects on the spermatogenesis and the appearance of testicular autoantibodies in three affected subjects (two brothers, aged 18 and 15 years, and their father, aged 48 years). The father and one of the brothers, who had peripubertal unilateral testicular torsion, presented normal fertility and oligozoospermia, respectively. The other brother, who had a history of bilateral testicular torsion, did not present pubertal development until he was 18 years old and he needed substitutive testosterone therapy. Sperm autoantibody titer increased only in the two cases with unilateral torsion and remained unmodified at a 5-year follow-up. The results indicate that testicular torsion can cause variable degrees of spermatogenesis impairment and induce development of autoantibodies against spermatozoa and gonadal antigens. The persistence of fertility in the father and the progressive spermatogenesis recovery in one of the affected sons suggest that the damaging effects of these autoantibodies deserve further investigation.

[Antisperm antibodies in prepubertal patients]. / Anticuerpos antiesperma en pacientes en edad prepuberal.

Antisperm antibodies were studied in 44 patients with less than 14 years of age, with unilateral testicle torsion and other testicular pathologies with vascular and inflammatory processes. The clinical and evolution of testicular size after one year of initial evaluation were obtained. Four cases had positive antisperm antibodies: One testicular torsion, two acute orchitis and one varicocele. In all the cases including those with positive antibodies the testicular size was normal in both sides. These findings agree with the theory of initiation of autoimmune process after a unilateral testicular damage, although we can not give data to support any damage to the contralateral testes.

[Spermatic cord torsion]. / Torsione del funicolo spermatico.

Spermatic cord torsion happens rather frequently in young men. It must be discovered early on, to allow for the possibility of removal by surgery. It appears from recently written medical articles that the endocrine function of the testis is protected following several hours of torsion and the risk of immunological damage to the contralateral testis is subsequently reduced.

[Histological and immunohistochemical studies on the damage of contralateral testis following the unilateral testicular torsion in Wistar rats].

The effect of experimental unilateral torsion of the testis on the contralateral intrascrotal testis in Wistar rats was evaluated histologically and immunohistochemically. The results were summarized as follows. 1) Histological damage of the seminiferous tubules in the contralateral testis was present only in adult rats. 2) The histological change 3-5 weeks after the experimental torsion consisted of marked decrease of spermatocytes, loss of spermatids and spermatozoa and numerous Sertoli-cell only tubules. Hyperplasia of the interstitial cells was demonstrated without thickness of the basement membrane and infiltration of the inflammatory cells. The tubular diameter and the ratio of contralateral testicular weight to rat body weight were significantly decreased (p less than 0.05) in torsion group. 3) Using an indirect immunofluorescent method, the positive immunohistochemical staining on spermatid and spermatozoa of normal testicular tissue was demonstrated using only the serum of rat with histological damage on the contralateral testis. Therefore, the phenomenon may be ascribable to the presence of antisperm antibody. It is concluded that the mechanism of the damage in seminiferous tubules of the contralateral testis with experimental torsion in adult Wistar rats is related to the humoral immunity producing antisperm antibody.

Spermatic cord torsion: effects of cyclosporine and prednisone on fertility and the contralateral testis in the rat.

Unilateral spermatic cord torsion results in contralateral degeneration and reduced fertility in the prepubertal male rat. This study was conducted to investigate the use of immunosuppression with cyclosporine and prednisone to prevent these untoward effects. Thirty-five-day-old male rats were subjected to 720 degrees unilateral spermatic cord torsion of 9 hours duration. At the time of detorsion, animals were given a subcutaneous injection of i) cyclosporine, ii) prednisone, or iii) cyclosporine combined with prednisone. Control groups included: i) animals undergoing orchiectomy of the ipsilateral testis following the torsion period, ii) hemicastration in the absence of torsion and iii) sham surgery. Orchiectomy at the end of the torsion period prevented the torsion induced reduction of fertility, contralateral seminiferous tubule diameter and testis weight. Treatment with cyclosporine combined with prednisone significantly increased these parameters above detorsion alone. These data indicate that short term immunosuppression with cyclosporine alone or in combination with prednisone limits the adverse effects of unilateral spermatic cord torsion as does removal of the damaged organ at the end of the torsion period.

New areas of research in male infertility.

Recent research in male reproduction holds much promise for future clinical application. Research on the relationship between sperm, semen, and the immune system may provide novel approaches to treating immune-related infertility. Investigations of sperm motility have shed new light on these complex mechanisms and may lead to rational approaches to the improvement of sperm function. New assays for secretory products unique to the testis show potential as markers for specific testicular cellular functions. In-vitro fertilization promises to become a viable treatment option for couples with male-factor infertility. Research on male contraception may lead to the development of safe and reversible male contraceptives.

Impaired spermatogenesis in testes at risk of torsion.

The oligospermia observed after unilateral torsion of the spermatic cord could reflect immunological damage to the opposite testis. An alternative explanation, that there may be a pre-existing defect in spermatogenesis, was tested in 20 post-pubertal males with acute torsion. In a prospective study the contralateral testis was biopsied at operation and the histological appearances were related to subsequent testicular function as assessed by seminal analysis 3 months later. Thirteen patients had biopsy evidence of partial maturation arrest in spermatogenesis which was either mild (6), moderate (4) or severe (3), and ten of these were oligospermic (less than 20 X 10(6)/ml). By contrast all seven patients with normal histology had a sperm concentration greater than 25 X 10(6)/ml. Histological grading of spermatogenesis by the Johnsen technique gave a higher score in patients with a normal biopsy (median 9.01, semi-quartile range 8.96-9.21) than in those with abnormal histology (median 8.28, semi-quartile range 7.98-8.45, P less than 0.001) and correlated with the log of the sperm concentration 3 months later (r = 0.79, P less than 0.001). There was minimal anti-sperm and no anti-testis antibody formation following torsion. Serum FSH levels were raised in 6 of 10 oligospermic patients, while all those with a normal sperm count had FSH concentrations within the normal range. Thus many patients who develop testicular torsion have an underlying defect in spermatogenesis, which correlates closely with poor postoperative exocrine function.