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Transplantation of wild-type spermatogonia leads to complete spermatogenesis in testes of cyclic 3',5'-adenosine monophosphate response element modulator-deficient mice.

The cAMP response element modulator (CREM) gene encodes transcription factors that are highly expressed in spermatids. A deficiency of the CREM gene leads to male infertility in mice due to round spermatid maturation arrest. However, CREM is also expressed in testicular Sertoli cells. We investigated whether CREM deficiency affects the germ line alone or whether the testicular environment is also dependent on CREM function. We examined the restoration of donor-derived spermatogenesis in CREM-deficient testes after transfer of wild-type spermatogonia (16 animals) and after transplantation of germ cells from CREM-deficient or heterozygous donors into spermatogenic tubules of wild-type hosts (16 and 12 animals). Six wk after endogenous spermatogenesis had been depleted by busulphan treatment, spermatogonia were transferred via the rete testis. Production of donor-derived germ cells in the deficient recipients was confirmed by testicular histology and polymerase chain reaction (PCR) analysis of testis fragments 7 and 13 wk after germ cell transfer. Sperm with donor genotype, as detected by PCR, also were flushed from the epididymis. Germ cell transfer using heterozygous donors was also successful. CREM-deficient germ cells largely failed to colonize wild-type recipient testes. According to these findings, germ cell differentiation is dependent on CREM function. The testicular environment of CREM-deficient mice is not essentially affected and is able to support complete spermatogenesis in the presence of wild-type germ cells.

Animals↗

Desmoplastic small round cell tumors of the paratesticular region. A report of six cases.

Desmoplastic small round cell tumor (DSRCT) typically occurs in the abdomen but may also present at other sites. We report six cases of paratesticular DSRCT. The patients, who ranged in age from 17 to 37 (mean, 28) years, presented with a scrotal mass (five cases) or testicular pain (one case). Grossly, the tumors were white to tan and firm. Typically, they involved the paratesticular soft tissue, serosal surfaces and the epididymis near the junction with the rete testis. Microscopically, the tumors consisted of nests of mitotically active "small blue cells" with scant cytoplasm embedded in a densely fibrotic stroma. Two tumors showed focal tubule formation; one of these also formed rosettes. The tumors exhibited the typical immunophenotype of DSRCT (positivity for keratin, vimentin, desmin, and neuron-specific enolase but nonreactivity with HBA-71 and anti-S-100). Four tumors metastasized to lymph nodes (retroperitoneal, cervical, and two unspecified); pulmonary metastases occurred in one of these cases and in one patient without lymph node metastases. One of the above patients treated with chemotherapy, died of disease at 16 months. The patients with pulmonary metastases (one of whom also had lymph node metastases) were treated with aggressive chemotherapy and are alive and apparently disease-free at 2.5 and 3 years, respectively. Three of the six patients, two of whom had known metastases, were lost to follow-up. The DSRCT of the paratestis has histologic and immunohistochemical features identical to its abdominal counterpart and must be differentiated from other "small blue cell" tumors of the paratesticular region.

Adolescent↗

Infarcted adenomatoid tumor: a report of five cases of a facet of a benign neoplasm that may cause diagnostic difficulty.

We describe five cases in which adenomatoid tumors showed extensive necrosis, presumably due to infarction, and posed diagnostic difficulty. The tumors occurred in four males (three with epididymal tumors and one with an intratesticular tumor) and one female (with a parafallopian tube tumor) 35 to 44 years of age. Two of the men presented with acute scrotal pain simulating epididymitis, and two with a palpable mass. The parafallopian tube tumor was an incidental finding. The tumors were solitary, grossly well-circumscribed, uniformly solid masses that ranged in size from 1.1 to 3.5 cm. Microscopically, they were all characterized by central necrosis with pale mummified adenomatoid tumor identified at least focally but often overshadowed by nondescript necrotic tissue. Viable adenomatoid tumor was identified in all cases but was minor in amount in two of them. The necrosis was surrounded by a florid reactive process of fibroblasts and myofibroblasts that had plump nuclei often with prominent nucleoli, and occasional mitoses. Two of the epididymal cases had adjacent rete testis showing epithelial hyperplasia with hyaline globule formation. The microscopic appearance often suggested the possibility of a malignant neoplasm because of: 1) blurring of the normal relatively easily identifiable junction between adenomatoid tumor and adjacent tissue; 2) irregular pseudo-infiltration of fat by reactive tissue and adenomatoid tumor; 3) paucity of typical adenomatoid tumor due to the infarction and the fact that viable tumor usually showed a solid pattern; and 4) atypia of the associated reactive cells. This unemphasized feature of adenomatoid tumors may potentially lead to more aggressive therapy than warranted if it is not correctly interpreted.

Adenomatoid Tumor↗

A conservative approach to bilateral testicular germ cell tumors.

We report on 6 patients with bilateral testicular germ cell tumors treated by organ sparing surgery. Tumors 6 to 30 mm. in diameter were enucleated, and biopsies of the tumor bed and peripheral parenchyma were taken. Histological examination revealed seminoma in 4 cases, embryonal carcinoma in 1 and a Leydig cell tumor in 1. All patients underwent testicular radiation therapy with 20 Gy. for carcinoma in situ. A testicular biopsy was performed 6 months postoperatively to evaluate therapeutic success. Median followup was 43 months, all patients were free of disease and there was no local recurrence. Luteinizing hormone and testosterone were within the normal range and no androgen substitution was necessary. Our study suggests that organ sparing surgery for bilateral testicular germ cell tumors represents a new therapeutic approach with endocrinological and psychological advantages. In our experience conservative surgery is possible under certain prerequisites, including organ confined tumor without infiltration of the rete testis, obtaining multiple biopsies of the tumor bed and peripheral parenchyma, associated carcinoma in situ treated by radiation therapy and close followup of patients.

Carcinoma, Embryonal↗

Sonography of benign intrascrotal lesions.

Ultrasound plays an important role and adds essential information in diagnosing benign intrascrotal lesions. Characterization of benign intrascrotal lesions with sonography, in combination with clinical assessment, can lead to nonsurgical management or testicular sparing surgery. We present important sonographic features of benign intrascrotal lesions, including extratesticular lesions: adenomatoid tumors, papillary cystadenomas, spermatoceles, hydroceles, varicoceles, hernias; and intratesticular lesions: tunica albuginea cysts, testicular simple cysts, epidermoid cysts, tubular ectasia of the rete testis, intratesticular varicoceles, adrenal rest tumors, and splenogonadal fusion. The goal of this review is to provide the radiologist with a better understanding of benign lesions that occur in the scrotum.

Diagnosis, Differential↗

Benign intrascrotal lesions.

PURPOSE: We summarize important clinical, pathological and diagnostic features of benign intrascrotal lesions, including paratesticular lesions (adenomatoid tumors, fibrous pseudotumors, cystadenomas, spermatoceles, hydroceles, varicoceles and hernias) and intratesticular lesions (tunica albuginea cysts, testicular simple cysts, epidermoid cysts, cystic ectasia of the rete testis, intratesticular varicocele, adrenal rest tumors and splenogonadal fusion). This review provides the reader with a better understanding of benign lesions that occur in the scrotum. MATERIALS AND METHODS: A directed MEDLINE literature review of benign scrotal lesions and of each individual lesion was performed. This information was enhanced with relevant information from select journals and texts. Particular emphasis was placed on clinical, pathological and diagnostic features. RESULTS: Intrascrotal lesions continue to provide a diagnostic challenge for physicians. A diagnosis can be made with a thorough history, physical examination and understanding of the pathophysiological processes of the structures contained within the scrotum. Lesions that are suspicious for malignancy should prompt urological consultation and radiological imaging. Ultrasound aids in the diagnosis in instances of uncertainty. Ultimately surgery may be necessary to make a histological diagnosis. CONCLUSIONS: Clinical assessment, physical examination and an understanding of benign intrascrotal processes are key to making a diagnosis. Ultrasound has an important role and adds essential information. If surgery is necessary and a benign process is recognized, a testis sparing procedure should be performed.

Adenomatoid Tumor↗

Retiform hemangioendothelioma: a case report and review of the literature.

BACKGROUND: Retiform hemangioendothelioma (RH) is a rare, recently described vascular neoplasm of low malignant potential. METHODS: We report a case of RH of the foot of a 19-year-old white female. Histologically, the tumor grew as numerous elongated vessels resembling the shape of rete testis with involvement of the skin adnexal structures and subcutaneous adipose tissue. No dissection of collagen by small groups of endothelial cells was seen. Wide local excision was performed and the patient was healthy with no metastasis at 14 months follow-up. RESULTS AND CONCLUSIONS: Our case is discussed in the context of previously reported cases of RH; we also include a review of all cases of RH published to date.

Adult↗

Heterogeneity in end-terminal sugars of rabbit and rat androgen binding protein (ABP).

The interaction between rabbit and rat androgen binding protein (ABP) and rabbit serum testosterone binding globulin (TeBG) with concanavalin A (Con A) was studied using affinity chromatography on Con A-Sepharose 4 B columns. When partly purified rat ABP, equilibrated with [3H]5 alpha-dihydrotesterone [3H]DHT was applied to Con A-Sepharose columns, approximately 50% of the ABP was retained by the column, whereas the remaining was eluted with the break-through protein fraction. A similar picture was found using partly purified rabbit ABP, or crude rabbit rete testis fluid. These studies indicate that both rat and rabbit ABP are glycoproteins, showing heterogeneity in their end-terminal sugars. When partly purified rabbit TeBG was examined by Con A-Sepharose affinity chromatography, the TeBG was completely retained by the column. The different elution patterns between rabbit ABP and rabbit TeBG indicate that these proteins, although showing identical physico-chemical and immunological properties (Weddington et al. 1975a,b), possess differences in their carbohydrate content.

Androgen-Binding Protein↗

Effect of androgens on the activity of acid hydrolases in rat epididymis.

The enzymatic activity of 6 acid hydrolases was studied in rat epididymal homogenates following castration, testosterone replacement and during postnatal growth. Acid phosphatase and N-acetyl-beta-D-glucosaminidase activity decreased after castration and increased with hormonal treatment as well as during growth. Beta-Glucuronidase and cathepsin D activity increased during the involution of the organ and decreased or did not change with hormone treatment or during sexual maturation. Arylsulphatase and deoxyribonuclease did not recover normal activity after hormonal treatment. Their activities were particularly high in epididymal and rete testis fluid of normal animals.

Acetylglucosaminidase↗

Early effects of efferent ductule ligation on the proximal segment of the rat epididymis.

The effects on the proximal caput epididymidis of efferent ductule ligation were studied. After 6 h there was a slight increase in autophagocytosis in the initial segment proper (1A). After 12 h this segment showed cell death and cytoplasmic regression and after 24 h large amounts of necrotic cells and focal degeneration in the epithelium, and desquamated cells and débris in the lumen. After 48 h the epithelium was lower, but degeneration less obvious. Segments 1B, 1C and 2 showed marked cell death and cytoplasmic degeneration. This was more evident after 3 days, especially in 1B. After 5 and 7 days some degeneration was still seen, but essentially regional differences had disappeared, leaving a lower, inactive epithelium throughout. Except for an increase in glycogen granules in segment 1C after 48 h, marked focal degeneration always appeared before general cytoplasmic alterations. Sham operation produced no changes. The regression might be caused by the cut supply of androgen binding protein or a growth factor in rete testis fluid.

Animals↗

Pharmacokinetic and pharmacodynamic studies of the effect of ketoconazole on reproductive function in male rats.

A single oral dose (300 mg kg-1) of ketoconazole induced reversible immobilization of rat epididymal spermatozoa at 8-24 h after dosing. This occurred when the drug concentrations in cauda epididymal fluid and seminal plasma were at their peak (18.0 +/- 7.3 and 13.5 +/- 3.0 micrograms ml-1, respectively), and which was preceded by a peak plasma concentration (Cmax) of 64.82 +/- 2.47 micrograms ml-1 at 5.15 +/- 0.68 h (Tmax). In contrast, rete testis fluid collected from the same animals contained only minute amounts of ketoconazole (0.47 +/- 0.34 micrograms ml-1). Plasma testosterone concentration showed a sharp decline within 4 h of dosing, followed by a recovery from suppression, even after administration of a low dose (100 mg kg-1) which did not affect sperm motility. These findings suggest that ketoconazole gains access to the post-testicular sex organs and affects the mature spermatozoa therein much more readily than it affects testicular spermatogenesis. Synthesis and screening of compounds with a related molecular structure but which exhibit more pronounced spermicidal and less pronounced anti-androgenic effects are thus suggested in the hope that rapidly acting and reversible male contraceptives might be identified and developed.

Administration, Oral↗

Male germ cell transplantation in rats: apparent synchronization of spermatogenesis between host and donor seminiferous epithelia.

Primordial germ cells (PGC) and gonocytes from male Sprague-Dawley rat fetuses and neonates were transplanted via the rete testis into the lumen of the seminiferous tubules of recipient adult Long Evans rats. The donor germ cells apparently differentiated into mini-tubules or irregular segments of seminiferous epithelium within the lumen of the host seminiferous tubules, and exhibited qualitatively normal spermatogenesis in 10 out of 16 recipients. The stage of spermatogenesis of the intraluminal epithelium was synchronized closely with that of the adjacent seminiferous tubule epithelium, suggesting that the spermatogenic cycle is regulated locally by the intraluminal microenvironment. Male germ cell transplantation provides an interesting new tool for investigating the control of spermatogenesis.

Animals↗

In-vitro initiation of forward motility in testicular spermatozoa.

Initiation of forward motility in vitro was investigated in goat and ram spermatozoa obtained from the rete testis. No forward motility was generated in the immotile testicular spermatozoa when they were incubated in a modified Ringer's solution containing theophylline (30 mM) and epididymal plasma (2 mg protein/ml). However, these reagents induced non-progressive flagellar movement in approximately 25% of spermatozoa. Bicarbonate (25 mM) induced forward motility in approximately 16% of the goat/ram testicular spermatozoa. Theophylline was essential for the bicarbonate-mediated activation of sperm motility, but epididymal plasma had no significant effect on this activation process. Theophylline activated progressive motility in testicular spermatozoa in a dose-dependent manner, the maximum effect occurring after incubation for 10 min with 30 mM theophylline. The initiation profile of in-vitro motility of goat/ram spermatozoa from the caput epididymis closely resembled that of testicular spermatozoa except that induction of motility in the caput spermatozoa was dependent both on bicarbonate and epididymal plasma. The data indicate that, unlike caput epididymal spermatozoa, initiation of motility in testicular spermatozoa is not dependent on motility-promoting protein(s) in epididymal plasma.

Animals↗

Immunohistochemical localization of the spermadhesin AWN-1 in the equine male genital tract.

Spermadhesins are proteins with various functions in sperm capacitation and zona pellucida binding. In this study the cellular localization of the spermadhesin AWN-1 has been examined in the equine male genital tract. Results obtained by immunohistochemical methods reveal that in the horse AWN-1 is synthesized in spermatogonia, in the rete testis, the ductus epididymidis and the seminal vesicles. These findings indicate that the cellular origin of spermadhesins is species-specific.

Animals↗

The resorptive activity in the bull efferent ductules--a morphological and experimental study.

The resorptive activity of the efferent ductules was studied in mature and immature bulls using histochemical, electron microscopical, and experimental methods. Resorptive activity was indicated by the uptake of the protein tracer (HRP) and the presence of microvilli, endocytotic apparatus, and alkaline phosphatase activity. The above features were found in all three types of nonciliated cells, but were apparently best developed in vacuolated (type III) cells. The resorptive apparatus was fully developed by 25 weeks, an age which roughly corresponds with the luminization of seminiferous tubules and the onset of spermatogenesis. In mature bulls the resorptive apparatus was markedly affected by androgen deprivation resulting from orchidectomy and was restored by the administration of testosterone, indicating its dependence upon the circulating androgen. Efferentiectomy had little impact, indicating that the luminal androgen does not play a major role in maintaining the resorptive apparatus. The tracer study revealed that the specific granules and vacuoles of type II and III cells, respectively, are not associated with resorptive function. It also showed that the tracer injected into the rete testis took 6 to 24 hours to pass through the efferent ductules and reach the initial segment of the epididymis.

Aging↗

Median raphe cyst in the scrotum, mimicking a serous borderline tumor, associated with cryptorchidism after orchiopecxy.

Median raphe cyst (MRC) is a benign lesion occurring predominantly in the ventral surface of the penises of young men and is an embryological developmental anomaly of the male genitalia. Serous borderline tumors (SBT) are found most frequently in the female ovary and only several cases with SBT of the male genitalia have been reported. We describe a case of MRC with features of SBT, which appeared in the scrotum of a 9-year-old boy after orchiopexy and was associated with surgery for cryptorchidism. The cyst arose on the right testicular tunica and consisted of cystic components with intracystic papillae lined by stratified epithelial cells, some of which showed mild cytological atypia and sporadic mitosis. These epithelial cells expressed CA 125, CA 19-9, carcinoembryonic antigen, estrogen receptor and progesterone receptor. Although no cases of MRC with characteristics of SBT in association with the rete testis has been described, the current report gives additional information for follow-up of cryptorchidism.

Child↗

Mechanisms of active suppression of the immune response to spermatozoa.

The production of autoantibodies to spermatozoa in males and isoantibodies in females is inhibited both by the physical isolation of spermatozoa from the systemic immune system and by active immunosuppression mechanisms. Lymphoid cells present in the epithelial lining of the rete testis, epididymis, and vas deferens, as well as the human ejaculate, are predominantly T suppressor/cytotoxic cells. Mononuclear cells derived from semen inhibit the in vitro activation of peripheral blood lymphocytes. Soluble specific T suppressor/cytotoxic cell activators in semen or on the sperm surface may be responsible for the predominance of this T cell subset in the male reproductive tract. The activation of T suppressor/cytotoxic cells following coitus may also limit the immune response to spermatozoa in females. Spermatozoa can also initiate immunosuppression, either by selectively inducing T suppressor cells or through the generation of activated complement components that block antibody production. Antisperm antibodies in sera from females may be associated with either a deficiency in the ability of their T suppressor/cytotoxic cells to be induced by factors in semen or by the occurrence in their husbands' ejaculates of microorganisms, antibodies, or other factors that induce T helper lymphocytes. Activated T cells produce interferon gamma, which induces Ia antigen expression on macrophages and allows the female's T helper cells to recognize processed sperm antigens. Recognition of the role of cell-mediated immune functions in the male and female genital tract identifies possible new target sites for the development of contraceptive agents.

Autoantibodies↗

Are estrogens carcinogenic during development of the testes?

Many chemicals in the environment mimic the female sex hormone, estrogen. Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for subsequent testicular disease, including neoplasia and poor semen quality. To understand the mechanisms of action of estrogenic chemicals during differentiation of the male genital tract, we have studied developmental exposure to the synthetic estrogen, diethylstilboestrol (DES). While DES is a much more potent estrogen than most environmental chemicals examined, several of these compounds share some of the same properties as DES, such as a relative lack of binding to serum estrogen carrying proteins. Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was observed in five percent of male mice treated in utero with DES. We also demonstrated altered regulation of an estrogen responsive gene, lactotransferrin (LTF) in the seminal vesicles of treated mice, but not the controls. Likewise, LTF was irreversibly altered in the uteri of developmentally treated females; at the molecular level altered methylation of the gene appears to be involved, thus, providing a potential marker for hormonal effects during development. The induction of permanent or "imprinted" responses during the development of a relatively estrogen-free reproductive tract cell suggests that undifferentiated targets for estrogen action may be sites for subsequent growth and differentiation defects associated with neoplasia.

Animals↗