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Background: Most infertile males with congenital bilateral absence of vas deferens (CBAVD) carry mutations on the cystic fibrosis transmembrane conductance regulator gene and may express mild cystic fibrosis (CF) symptoms. Barriers to paternity for these men can now be overcome by assisted reproduction. Our aims were to investigate the CF-related phenotype and clinical outcome for 50 patients with CBAVD seen at a CF adult centre between 1992 and 1999.Methods and Results: The investigation of the patients included screening for 22 CF mutations and identification of the poly-T variant of intron 8, sweat testing, clinical investigation for CF-related extra-genital manifestations, and genetic counselling. CFTR mutations were detected on 56 alleles of the 50 patients. A total of 15 (30%) was compound heterozygote and 26 (52%) heterozygote. In all, 38% of the patients had a positive sweat test. Four patients were diagnosed with typical CF not detected previously. Twenty-one patients became fathers following ICSI (eight cases), artificial insemination by donor or IVF with sperm donor (seven cases) or through adoption (six cases). A mail survey allowed the identification of CF-related clinical symptoms. Information on the occurrence of CF-related symptoms was obtained for 58.5% of patients: in the absence of initial symptoms, no new clinical signs were reported.Conclusion: Patients diagnosed with CBAVD need genetic counselling before assisted reproduction. Even when no wish for paternity is expressed, CF gene screening should be associated with at least a sweat test and clinical evaluation because of possible mild forms of CF disease. Medical follow-up did not reveal any new symptoms. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta (TGFbeta) is a cytokine with autocrine and paracrine action in the testis and potent immunoregulatory and anti-inflammatory activities. In the present study, we examined the concentration of latent (acid-activatable) and free (active) TGFbeta in seminal plasma from normal subjects (n = 23) and infertile (n = 40) patients, by using a TGFbeta specific immunoenzymological assay, and a bioassay (CCL64 cell line growth inhibition) detecting any form of TGFbeta. Free TGFbeta1 was present in normal subjects at a concentration (1.82 +/- 1.06 ng/ml) close to that known to give maximal stimulation in vitro. In pathological groups, the mean concentrations were not significantly different from the normal ones. Latent TGFbeta1 was present in normal seminal plasma at a high concentration (92.4 +/- 29.2 ng/ml). In subjects with pathologies of both testis and genital apparatus, or with epididymal occlusion, mean latent TGFbeta1 concentrations were normal, whereas transferrin concentrations were lower. The concentrations found in the epididymal occlusion group indicate that TGFbeta1 is, for a large part, secreted by the genital tract. In the testicular pathology group, TGFbeta1 concentrations were 130.7 +/- 61.2 ng/ml, a mean not statistically different from normal, although higher. No differences were found between patients with high and normal blood plasma follicle stimulating hormone, and this is consistent with the notion that most TGFbeta1 in seminal plasma is not of testicular origin. The TGFbeta bioassay ensured that immunologically detected TGFbeta was present in a bioactive or bioactivatable form. Furthermore, the values found in normal and pathological seminal plasmas were usually higher than those detected by the immunoassay, suggesting that other forms of TGFbeta might be present. Together, the present data show that very large amounts of TGFbeta are present in human seminal plasma. The TGFbeta ligand assay in the seminal plasma appears to indicate no differences between normal and infertile subjects. [ABSTRACT FROM AUTHOR]

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Hypogonadism affects an estimated 2-4 million men in the USA, but only 5% receive treatment. Testosterone replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch(®) ). The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer)., Objective: To assess the change in prostate-specific antigen (PSA) concentrations in patients with primary or secondary hypogonadism, receiving transdermal testosterone., Patients and Methods: This was an interventional, 6-year study, conducted in Urology and Endocrinology centres in Belgium, France, Germany, the Netherlands and Spain. Participants were primary (48%) or secondary (52%) hypogonadal patients who received two 60 cm(2) testosterone patches (Testopatch(®) ), delivering 4.8 mg of testosterone per day, applied every 2 days. During treatment, total testosterone (TT), dihydrotestosterone, oestradiol and, PSA concentrations were measured in a centralised laboratory every 3 months during the first year, and every 6 months thereafter., Results: In all, 200 patients [mean (sd) age 41.0 (12.5) years, body weight 82.5 (13.7) kg, height 177.2 (9.3) cm, body mass index 26.2 (3.4) kg/m(2) ] were treated with transdermal testosterone patches. In all, 161 patients completed the 1-year study and 115 entered into a 5-year study extension; 51 patients completed the sixth year of the study. The mean baseline concentrations of TT and PSA were 1.4 ng/mL and 0.47 ng/mL, respectively; TT serum concentrations >3 ng/mL were achieved in 85% of patients and fluctuated between 4.4 and 6.0 ng/mL. At each successive 6-month time point, mean the PSA values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71, 0.75, 0.74, 1.01, 0.78, 0.80 ng/mL, respectively. The mean PSA velocity was negligible (0.00-0.03 ng/mL/year) from 30 months to the end of the trial, except for a value of 0.08 at 60 months. Seven patients had a PSA concentration of >4 ng/mL due to a sharp PSA increase. Six of these patients had prostatitis and PSA concentrations returned to previous levels with appropriate treatment. No prostate cancer was reported during the trial., Conclusion: These data support a strong safety profile for Testopatch, even at the highest registered dosage., (© 2013 BJU International.)

Background: The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma., Methods: Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics., Results: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation., Conclusions: Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.

Objective: To localize the different proteins involved in the executioner step of apoptosis in the human testicular tissue: effector caspases (3, 6, and 7), caspase inhibitors called inhibitor of apoptosis proteins (IAPs, such as XIAP), and IAP inhibitors such as Smac/DIABLO and to investigate XIAP and Smac expression and activation of caspase-3 in azoospermia., Design: Retrospective study., Setting: The Biology of Reproduction Center of Poissy and Inserm U407, France., Patient(s): Twenty-five patients diagnosed as azoospermic and 4 patients with normal testicular histology., Intervention(s): Testicular biopsies for histopathological assessment., Main Outcome Measure(s): Localization of proteins by immunohistochemistry., Result(s): Effector caspase-7 seemed to be absent from normal human testes, whereas procaspase-3 and procaspase-6 were detected in both somatic and germ cells. XIAP was mainly expressed in Sertoli cells, whereas its inhibitor Smac was detected in pachytene spermatocytes. On the other hand, although few apoptotic germ cells were detected in biopsies from patients with obstructive azoospermia, increased levels of apoptotic germ cells were detected in spermatogenetic arrest. This increase in apoptotic germ cells was associated with increased levels of active caspase-3 in patients with spermatogenetic arrest, whereas the expression of XIAP and Smac/DIABLO was at similar levels in all groups., Conclusion(s): Active caspase-3 might be important in the apoptotic process observed in spermatogenetic arrest.

Objectives: To study long-term efficacy and safety of a testosterone-in-adhesive matrix patch, delivering 4.8 mg of testosterone daily., Methods: Randomized, open label, multicenter 1-year study. 224 hypogonadal patients were included. 188 received 2 patches of 60 cm2 every 48 h and 36 patients had IM testosterone enanthate injection every 3 weeks. T, bioavailable T (BT), DHT, E2, LH, FSH and SHBG and clinical symptom scores (AMS and MSF-4) were assessed at 3, 6 and 12 months., Results: In the patch group, T serum levels were above 3 ng/mL in 85% of patients and remained stable over time. BT, DHT and E2 levels were restored within physiological range. BT/T ratio varied from 20 to 70%. In the IM group, the percentages of "normalized" patients appeared to be lower, although the two groups cannot be adequately compared due to the kinetic profile of T following IM administration, resulting in greater variations of serum T levels, blood samplings occurring randomly at time of peak, trough, or in between. A significant correlation was found between T, BT and the MSF-4 changes. BT levels were significantly related to total AMS score. PSA values showed a mean (S.D.) increase of 0.13 (0.38), 0.23 (0.79) and 0.30 (1.47)ng/mL at weeks 14, 27 and 53, respectively. The patch was well tolerated with no negative impact either on lipid profile, or red blood cells. Administration site reactions occurred in 35 patients (18.8%). Adhesiveness was good (>or=75%) in >90% patients over the 1 year application period., Conclusion: Two 60 cm2 patches, allowed constant physiological levels of sexual hormones over time. This new patch was well tolerated, easy to use, well accepted by the patients and displayed a very good adhesiveness. Clinical efficacy was more related to BT than to T.

Reactive oxygen species (ROS) have a negative impact on sperm DNA, leading to the formation of oxidative products such as 8-oxo-7,8-dihydroxyguanosine. This compound causes fragmentation and, thus, has a mutagenic effect. Patient treatment with oral antioxidant vitamins is, therefore, standard practice for male infertility, in an attempt to decrease formation of ROS and improve fertility. In this study, the DNA fragmentation index and the degree of sperm decondensation were measured using the sperm chromatin structure assay before and after 90 days treatment with antioxidant vitamins associated with zinc and selenium. Antioxidant treatment led to a decrease in sperm DNA fragmentation (-19.1%, P < 0.0004), suggesting that at least part of the decay was linked to ROS. However, it also led to an unexpected negative effect: an increase in sperm decondensation with the same order of magnitude (+22.8%, P < 0.0009). The opening of interchain disulphide bridges in protamines may explain this aspect, as antioxidant vitamins, especially vitamin C, are able to open the cystin net, thus interfering with paternal gene activity during preimplantation development. This observation might explain the discrepancy observed concerning the role of these antioxidant treatments in improving male fertility.