The production of glial cell line-derived neurotrophic factor by human sertoli cells is substantially reduced in sertoli cell-only testes.

STUDY QUESTION: Do human Sertoli cells in testes that exhibit the Sertoli cell-only (SCO) phenotype produce substantially less glial cell line-derived neurotrophic factor (GDNF) than Sertoli cells in normal testes? SUMMARY ANSWER: In human SCO testes, both the amounts of GDNF mRNA per testis and the concentration of GDNF protein per Sertoli cell are markedly reduced as compared to normal testes. WHAT IS KNOWN ALREADY: In vivo, GDNF is required to sustain the numbers and function of mouse spermatogonial stem cells (SSCs) and their immediate progeny, transit-amplifying progenitor spermatogonia. GDNF is expressed in the human testis, and the ligand-binding domain of the GDNF receptor, GFRA1, has been detected on human SSCs. The numbers and/or function of these stem cells are markedly reduced in some infertile men, resulting in the SCO histological phenotype. STUDY DESIGN, SIZE, AND DURATION: We determined the numbers of human spermatogonia per mm2 of seminiferous tubule surface that express GFRA1 and/or UCHL1, another marker of human SSCs. We measured GFRA1 mRNA expression in order to document the reduced numbers and/or function of SSCs in SCO testes. We quantified GDNF mRNA in testes of humans and mice, a species with GDNF-dependent SSCs. We also compared GDNF mRNA expression in human testes with normal spermatogenesis to that in testes exhibiting the SCO phenotype. As controls, we also measured transcripts encoding two other Sertoli cell products, kit ligand (KITL) and clusterin (CLU). Finally, we compared the amounts of GDNF per Sertoli cell in normal and SCO testes. PARTICIPANTS/MATERIALS SETTING METHODS: Normal human testes were obtained from beating heart organ donors. Biopsies of testes from men who were infertile due to maturation arrest or the SCO phenotype were obtained as part of standard care during micro-testicular surgical sperm extraction. Cells expressing GFRA1, UCHL1 or both on whole mounts of normal human seminiferous tubules were identified by immunohistochemistry and confocal microscopy and their numbers were determined by image analysis. Human GDNF mRNA and GFRA1 mRNA were quantified by use of digital PCR and Taqman primers. Transcripts encoding mouse GDNF and human KITL, CLU and 18 S rRNA, used for normalization of data, were quantified by use of real-time PCR and Taqman primers. Finally, we used two independent methods, flow cytometric analysis of single cells and ELISA assays of homogenates of whole testis biopsies, to compare amounts of GDNF per Sertoli cell in normal and SCO testes. MAIN RESULTS AND THE ROLE OF CHANCE: Normal human testes contain a large population of SSCs that express GFRA1, the ligand-binding domain of the GDNF receptor. In human SCO testes, GFRA1 mRNA was detected but at markedly reduced levels. Expression of GDNF mRNA and the amount of GDNF protein per Sertoli cell were also significantly reduced in SCO testes. These results were observed in multiple, independent samples, and the reduced amount of GDNF in Sertoli cells of SCO testes was demonstrated using two different analytical approaches. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: There currently are no approved protocols for the in vivo manipulation of human testis GDNF concentrations. Thus, while our data suggest that insufficient GDNF may be the proximal cause of some cases of human male infertility, our results are correlative in nature. WIDER IMPLICATIONS OF THE FINDINGS: We propose that insufficient GDNF expression may contribute to the infertility of some men with an SCO testicular phenotype. If their testes contain some SSCs, an approach that increases their testicular GDNF concentrations might expand stem cell numbers and possibly sperm production. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Centers for Translational Research in Reproduction and Infertility Program (NCTRI) Grant 1R01HD074542-04, as well as grants R01 HD076412-02 and P01 HD075795-02 and the U.S.-Israel Binational Science Foundation. Support for this research was also provided by NIH P50 HD076210, the Robert Dow Foundation, the Frederick & Theresa Dow Wallace Fund of the New York Community Trust and the Brady Urological Foundation. There are no competing interests.

[Testosterone and prostate]. / Testostérone et prostate.

Age related testosterone deficiency syndrome may occur with other diseases of the elderly men, as prostate diseases. The relationship between testosterone and prostate has been widely studied the last 10 years, with the increased use of testosterone replacement therapy. The traditional belief that testosterone administration causes prostate cancer growth has been challenged by recent studies. To date, nothing has been found to support the evidence that restoring testosterone levels within physiological range increases the incidence of prostate cancer in hypogonadic patients. In these patients, testosterone replacement therapy does not seem to worsen lower urinary tract symptoms.

Indication, surgical technique and outcome of orthotopic renal transplantation.

PURPOSE: We review the indication, surgical technique and outcome of orthotopic renal transplantation. MATERIALS AND METHODS: The medical records of 1,000 patients who underwent renal transplantation at our institution between August 24, 1993 and August 1, 2000, as well as orthotopic renal transplantation were reviewed. RESULTS: Orthotopic renal transplantation was performed in 4 males and 1 female with severe iliac atherosclerosis or retained bilateral iliac fossa kidney transplant. Mean patient age was 56 years. There were 2 patients who received kidneys from living related donors, and 3 underwent cadaveric renal transplantation. Left orthotopic renal transplantation was successful in 4 cases, and 1 was converted to iliac fossa renal transplant because of a pulseless splenic artery and renal artery thrombosis after native renal endarterectomy. Orthotopic renal revascularization was done with splenic artery in 2, native renal artery in 2 and left renal vein in all 4 patients. Urinary tract reconstruction was performed with stented (2) or nonstented (2) ureteroureterostomy. Antibody induction, purine antagonists, calcineurin inhibitors and glucocorticoids were used for immunosuppression. Mean preoperative and 1-month postoperative serum creatinine was 7.9 and 1.3 mg./dl., respectively. Patient and graft survival was 100% during followup, which ranged from 6 months to 5 years. CONCLUSIONS: Despite the technical challenges, orthotopic renal transplantation in patients with unsuitable pelvic vessels can result in excellent patient and graft survival.

Recurrence of varicocele after high retroperitoneal repair: implications of intraoperative venography.

PURPOSE: We determined whether intraoperative venography results in a decreased recurrence rate after varicocele repair in adolescence. MATERIALS AND METHODS: We evaluated 177 male adolescents 14 to 19 years old who underwent varicocele repair via the high retroperitoneal approach with artery sparing and intraoperative venography. RESULTS: Overall the recurrence rate was 2.8% (5 of 177 cases) in the venography group and 11% in historical controls without venography. We identified left-to-right cross communicating vessels in 3 patients with recurrence. Intraoperatively venography revealed nonligated vessels in 21 patients (12%), resulting in revision and repair during the same procedure. CONCLUSIONS: Intraoperative venography seems to decrease the rate of recurrence. Left-to-right cross communicating vessels may be present in some adolescents with recurrence after varicocelectomy.

Current management of adolescent varicocele.

The finding of varicocele in an adolescent male is common. Varicocele rarely causes symptoms and is often diagnosed on the routine physical examination. There is clear association between varicocele and male factor infertility; however, there is debate about whether, when, and whom to treat when present in adult or adolescent males. This review of the epidemiology, etiology, pathophysiology, and treatment of the adolescent with varicocele will provide the reader with tools to make appropriate decisions in dealing with this condition.

Stages at presentation, prognostic factors, and outcome of breast cancer in males.

BACKGROUND: In order to support or refute conventional notions of breast cancer in males as a late-presenting disease associated with a worse prognosis than the same disease in females, we reviewed a recent, multi-institutional experience. METHODS: A case series from three area hospital system cancer data bases was reviewed. Demographics, pathology, stages at presentation, and treatment were determined from the data set and correlated with outcomes (recurrence/survival). RESULTS: Fifty-four patients (mean age 64.5, SD = 12.8) were identified; half of the tumors were stage T0 or T1, 62% were node negative (N0), and 57% had an American Joint Committee on Cancer (AJCC) stage grouping of IIA or less. Eighty-five percent of tumors examined expressed hormone receptors. There were no local-only recurrences in the 50 cases resected for cure, including 5 cases of minimal breast cancer treated by lumpectomy only. Five- and 10-year overall disease-free survival was AJCC stage related: 100% and 71%, respectively, for early stage (0-IIA) disease, and 71% and 20%, respectively, for advanced (IIB-IV) stage (P = 0.0051 by log-rank). Only AJCC stage and its components (tumor size, nodal status, presence of metastases) correlated with survival by multivariate analysis; other factors such as age, family history, and presenting symptoms/signs did not. CONCLUSIONS: The majority of breast cancers in males present at early stages and are hormone receptor positive. In contrast to older notions of this disease as uniformly aggressive, we conclude that prognostic factors and stage-for-stage outcomes for breast cancer in males are similar to those published for the disease in females.

Repair versus observation in adolescent varicocele: a prospective study.

PURPOSE: We designed a randomized prospective study of male adolescents with moderate and severe varicoceles to determine whether prophylactic varicocele repair is beneficial. MATERIALS AND METHODS: We evaluated 2,100 boys (10 to 20 years old) for genitourinary abnormalities. From this population 2 groups of adolescents 15 to 19 years old with grade 2 or 3 varicoceles were created, including 88 who underwent varicocele repair and 36 controls. Testicular volume and pampiniform vein diameter were measured, and Doppler ultrasound was performed. RESULTS: After 12 months volume of the involved left testis increased to almost normal in treated boys (mean atrophy index 12.7% at surgery and 3% 12 months later). In controls the corresponding atrophy indexes were 10 and 9%, respectively. The relative increase in left testicular volume was 26% in the surgery group and 11% in controls. In the surgery group mean pampiniform vein diameter decreased from 2.8 preoperatively to 2 mm. postoperatively but there was no change in controls. CONCLUSIONS: Varicocele repair in adolescents with moderate and severe varicocele reversed testicular growth arrest and resulted in catch-up growth within 12 month of surgery.

Assessment of adolescent varicocele.

Varicocele is the most important male factor responsible for decreased fertility potential in married couples. From March through June 1994, 2,470 school boys aged 10-20 years were examined to establish the incidence of consecutive grades of varicocele and to develop a protocol for diagnosis and treatment of adolescents with varicocele. Grade 1 varicocele was found in 18%, grade 2 in 12%, and grade 3 in 5% of the population examined. An original protocol of ultrasonographic (US) examination (previously verified by angioscintigraphy) was introduced to assess boys with clinically diagnosed varicocele. The volume of each testis, testicular volume decrease (TVD), pampiniform vein diameter (PVD), and basal (BBF) and maximum blood flow (MBF) velocities were measured in 625 boys. In 74 cases a semen analysis was performed. The statistical analysis revealed that the presence of venous reflux and PVD correlated with the grade of varicocele. Decreases in testicular volume were highly dependent on the grade of varicocele, PVD, and BBF and MBF velocities. Analysis of the relationship between spermatic (boys over 17 years) and US findings revealed that the quality of spermatogenesis can be predicted by US examination in adolescents with varicocele. The authors recommend multiparametric US examination as a reliable, objective, and repeatable technique for establishing criteria for operative treatment in boys under 18 years of age with varicocele as well as for postoperative evaluation.

Semen analysis in young men with varicocele: preliminary study.

PURPOSE: Our aim was to determine whether the deleterious effect of varicocele on spermatogenesis, as reflected by semen analysis, occurs in boys as young as 17 to 19 years. Data analysis was done of semen variables of select boys attending randomly chosen schools. MATERIALS AND METHODS: A total of 36 healthy boys without a pathological condition detected by history, physical examination and scrotal ultrasound served as controls, and 38 with profound varicocele who were otherwise healthy served as an experimental group. All boys were followed as outpatients 2 times during the last year. We performed semen and clinical examinations, Doppler ultrasound assessment of venous reflux, and ultrasound measurement of testicular and pampiniform vein diameters. RESULTS: No significant differences were found in sperm concentration, volume, presence of spontaneous agglutination and pH between the 2 groups. There were significant differences in total and progressive sperm motility and vitality, which were lower in boys with varicocele, as were the number of normal sperm forms. There was a statistically and clinically significant linear negative relationship between sperm motility, and maximal and basal blood flow velocities as well as pampiniform vein diameter. CONCLUSIONS: Varicocele can affect spermatogenesis in boys as young as 17 to 19 years, as shown by the decrease in motility, vitality and number of normal forms of spermatozoons. The clinically significant correlations between semen analysis parameters and ultrasound findings allow the prediction of testicular function using ultrasound alone.